Heteroarylcarboxylic acid ester derivative

ABSTRACT

Compounds represented by formula (I): 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the description, and pharmaceutically acceptable salts thereof are useful as hyperglycemic inhibitors having a serine protease inhibitory action and as prophylactic or therapeutic drugs for diabetes.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 14/496,363, filed Sep.25, 2014, which is a continuation of Ser. No. 14/089,040, filed Nov. 25,2013, now U.S. Pat. No. 8,877,805, which is a continuation of Ser. No.13/484,822, filed May 31, 2012, now U.S. Pat. No. 8,609,715, which is acontinuation of International Patent Application No. PCT/JP2010/071929,filed on Dec. 7, 2010, and claims priority to Japanese PatentApplication No. 2009-277827, filed on Dec. 7, 2009, and Japanese PatentApplication No. 2010-214406, filed on Sep. 24, 2010. All of the aboveapplications are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention Description

The present invention relates to novel heteroarylcarboxylic acid esterderivatives having a serine protease (particularly trypsin andenteropeptidase) inhibitory activity. The present invention also relatesto pharmaceutical compositions which contain such a heteroarylcarboxylicacid ester derivative and drugs for the treatment or prophylaxis ofdiabetes. The present invention further relates to methods for thetreatment and/or prophylaxis of diabetes by administering such aheteroarylcarboxylic acid ester derivative.

2. Discussion of the Background

At present, insulin secretagogues (sulfonylurea), glucose absorptioninhibitors (a-glucosidase inhibitor), insulin sensitizers (biguanide,thiazolidine derivative), and the like are clinically used astherapeutic drugs for diabetes. However, since all of them areaccompanied by side effects such as 35 hypoglycemia, diarrhea, lacticacidosis, edema, and the like, show an insufficient effect, and thelike, a medicament satisfying clinical needs is still demanded.

In recent years, a benzoic acid ester having a protease inhibitoryactivity, which is represented by the following compound, has beenreported to show a blood glucose elevation suppressing action indiabetes animal model (see WO2006/057152, which is incorporated hereinby reference in its entirety).The following compound is considered to show an enzyme inhibitoryactivity on trypsin, thrombin, pancreatic, and plasma kallikreins,plasmin and the like and a leukotriene receptor antagonistic action.Moreover, an enteropeptidase inhibitory activity of the followingcompound has also been reported (see Biomedical Research (2001), 22(5)257-260, which is incorporated herein by reference in its entirety).However, many unclear points remain in the relationship between suchactions and a blood glucose elevation suppressing action.

On the other hand, as for a heteroarylcarboxylic acid ester structure,JP-A-55-161385, which is incorporated herein by reference in itsentirety, discloses a compound as a therapeutic drug for pancreatitis.In this document, only heteroarylcarboxylic acid ester compounds whereinthe substituent of the heteroarylcarboxylic acid moiety is a methylgroup or a methoxy group or unsubstituted compounds are disclosed, asrepresented by the following formula. While these compounds aredisclosed as showing an inhibitory activity on trypsin, chymotrypsin andthrombin, no description is given as to the enteropeptidase inhibitoryactivity and blood glucose elevation suppressing action.

In addition, Advances in Experimental Medicine and Biology (1989), 247B(Kinins 5, Pt. B), 271-6, which is incorporated herein by reference inits entirety, also describes a heteroarylcarboxylic acid ester having aprotease inhibitory activity, which is represented by the followingformula. However, only compounds wherein the heteroaryl moiety isunsubstituted are disclosed, and no description is given as to theenteropeptidase inhibitory activity and blood glucose elevationsuppressing action of these compounds.

Furthermore, WO99/41231, which is incorporated herein by reference inits entirety, describes a compound represented by the following formula.However, it has a structure wherein an aryl group substituted by acarboxyl group is directly bonded to the heteroaryl moiety, which iscompletely different from the compound of the present invention. Thedocument discloses an inhibitory activity against blood coagulationfactor VIIa; however, no description is given as to the enteropeptidaseinhibitory activity and blood glucose elevation suppressing action.

On the other hand, trypsin is one of the intestinal serine proteases andis produced by degradation of inactive trypsinogen by enteropeptidase.Trypsin is known to activate various digestive enzymes by acting onchymotrypsinogen, proelastase, procarboxylesterase, procolipase andpro-sucrase-isomaltase, and the like. Therefore, it is considered thatan inhibitor of enteropeptidase and trypsin lowers the digestivecapacity for protein, lipid, and carbohydrates, and is effective as adrug for the treatment or prophylaxis of obesity and hyperlipidemia.

WO2006/050999, which is incorporated herein by reference in its entiretydescribes that a medicament that inhibits both enteropeptidase andtrypsin is interesting as a body fat-reducing agent. In addition,WO2009/071601, which is incorporated herein by reference in its entiretyreports a compound having an inhibitory activity againstenteropeptidase, trypsin, plasmin, kallikrein, and the like as anantiobesity drug. However, neither of these publications describesuppression of blood glucose elevation and hypoglycemic effect affordedby simultaneous inhibition of enteropeptidase and trypsin, and theprotease inhibitor described therein has a structure completelydifferent from that of the compound of the present invention.

Accordingly, there remains a need for compounds which are useful for thetreatment or prophylaxis of diabetes. Therefore, to further satisfy theclinical needs from the aspects of effect, safety and the like, ahyperglycemic inhibitor having a serine protease inhibitory action,which is a new drug for the treatment or prophylaxis of diabetes, isdesired.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelcompounds which are useful for the treatment or prophylaxis of diabetes.

It is another object of the present invention to provide novel compoundshaving a serine protease inhibitory action.

It is another object of the present invention to provide novel serineprotease (particularly trypsin and enteropeptidase) inhibitors.

It is another object of the present invention to provide novelhyperglycemic inhibitors or hypoglycemic agents, and further, drug forthe treatment and/or prophylaxis of any of diabetes, obesity,hyperlipidemia, diabetic complication, and metabolic syndrome.

It is another object of the present invention to provide novel methodsfor the treatment and/or prophylaxis of any of diabetes, obesity,hyperlipidemia, diabetic complication, and metabolic syndrome.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the heteroarylcarboxylic acid ester derivatives described belowhave serine protease inhibitory activity and are useful for thetreatment and/or prophylaxis of any of diabetes, obesity,hyperlipidemia, diabetic complication, and metabolic syndrome.

Thus, in view of the above-mentioned current situation, the presentinventors have conducted intensive studies and considered thatsimultaneous inhibition of trypsin and enteropeptidase is particularlyeffective for the suppression of blood glucose elevation. They havesynthesized various heteroarylcarboxylic acid ester derivatives, whichare novel compounds, evaluated trypsin and enteropeptidase inhibitoryactivity, and found that certain heteroarylcarboxylic acid esterderivatives are protease inhibitors that simultaneously inhibit them,which resulted in the completion of the present invention. Furthermore,they have also found that such representative compounds show a bloodglucose elevation suppressing effect in diabetes animal model.

Accordingly, the present invention provides a heteroarylcarboxylic acidester derivative represented by the following formula (I):

wherein

R1, R2, R3, and R4 may be the same or different and are eachindependently a hydrogen atom, a nitro group, a halogeno group, a cyanogroup, a hydroxyl group, a thiol group, an amino group, a guanidinogroup, a formyl group, a lower alkyl group, a lower alkenyl group, alower alkynyl group, a lower acyl group, a carboxyl group, a sulfogroup, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower acyloxy group, a loweracylamino group, a lower alkoxycarbonyl group, a carbamoyl group, alower alkylcarbamoyl group, a lower alkylsulfonylamino group, or asulfamoyl group,

HetAr is a heteroaromatic ring optionally having substituent(s),

X is a lower alkylene group optionally having substituent(s), a loweralkenylene group optionally having substituent(s), a lower alkynylenegroup optionally having substituent(s), a phenylene group, or athiophenylene group,

Y is a carbonyl group, a thiocarbonyl group, or a sulfonyl group, and

A is —OR5 (R5 is a hydrogen atom or a lower alkyl group);

a group of the following formula (II):

wherein R6 and R7 may be the same or different and are eachindependently a hydrogen atom, a hydroxyl group, a lower alkyl groupoptionally having substituent(s), a lower alkenyl group optionallyhaving substituent(s), a lower alkynyl group optionally havingsubstituent(s) or a lower alkoxyl group optionally havingsubstituent(s), or R6 and R7 may be bonded to form a cyclic amino groupoptionally having substituent(s);

a group of the following formula (II-2):

—U—CH(R6′)R7′  (II-2)

wherein U is O or S, and R6′ and R7′ may be the same or different andare each independently a hydrogen atom, a hydroxyl group, a carboxylgroup, a lower alkyl group optionally having substituent(s), a loweralkenyl group optionally having substituent(s), a lower alkynyl groupoptionally having substituent(s) or a lower alkoxyl group optionallyhaving substituent(s), or R6′ and R7′ may be bonded to form a cyclicamino group optionally having substituent(s); or

a group of the following formula (II-3):

—NH—N(R6″)R7″  (II-3)

wherein R6″ and R7″ may be the same or different and are eachindependently a hydrogen atom, a hydroxyl group, a lower alkyl groupoptionally having substituent(s), a lower alkenyl group optionallyhaving substituent(s), a lower alkynyl group optionally havingsubstituent(s) or a lower alkoxyl group optionally havingsubstituent(s), or R6″ and R7″ may be bonded to form a cyclic aminogroup optionally having substituent(s),

or a pharmaceutically acceptable salt thereof (hereinafter sometimes tobe simply referred to as “the compound of the present invention”), apharmaceutical composition containing the same, or a serine proteaseinhibitor containing the same as an active ingredient.

The present invention also provides a compound represented by theaforementioned formula (I) wherein

R1, R2, R3, and R4 may be the same or different and are eachindependently a hydrogen atom, a nitro group, a halogeno group, a cyanogroup, a hydroxyl group, a thiol group, an amino group, a guanidinogroup, a formyl group, a lower alkyl group, a lower alkenyl group, alower alkynyl group, a lower acyl group, a carboxyl group, a sulfogroup, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower acyloxy group, a loweracylamino group, a lower alkoxycarbonyl group, a carbamoyl group, alower alkylcarbamoyl group, a lower alkylsulfonylamino group, or asulfamoyl group,

HetAr is a heteroaromatic ring optionally having substituent(s),

X is a lower alkylene group optionally having substituent(s), a loweralkenylene group optionally having substituent(s), or a lower alkynylenegroup optionally having substituent(s),

Y is a carbonyl group, a thiocarbonyl group, or a sulfonyl group, and

A is —OR5 (R5 is a hydrogen atom or a lower alkyl group), or a group ofthe following formula (II):

wherein R6 and R7 may be the same or different and are eachindependently a hydrogen atom, a hydroxyl group, a lower alkyl groupoptionally having substituent(s), a lower alkenyl group optionallyhaving substituent(s), a lower alkynyl group optionally havingsubstituent(s) or a lower alkoxyl group optionally havingsubstituent(s), or R6 and R7 may be bonded to form a cyclic amino groupoptionally having substituent(s),

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein R1, R2, R3, and R4 are eachindependently a hydrogen atom, a nitro group or a halogeno group,

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein HetAr is a 5- to 10-membered aromaticring containing 1 to 3 hetero atoms, which optionally hassubstituent(s),

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein -HetAr- is a heteroaromatic ringgroup represented by the following formula (III-1) or (III-2):

wherein Z1 and Z2 are each independently CRa or a nitrogen atom, and Z3is an oxygen atom, a sulfur atom, or NRb, wherein Ra and Rb may be thesame or different and are each independently a hydrogen atom, a nitrogroup, a halogeno group, a cyano group, a hydroxyl group, a thiol group,an amino group, a guanidino group, a formyl group, a lower alkyl group,a lower alkenyl group, a lower alkynyl group, a lower acyl group, acarboxyl group, a sulfo group, a phosphono group, a lower alkoxyl group,a lower alkylthio group, a lower alkylamino group, a lower acyloxygroup, a lower acylamino group, a lower alkoxycarbonyl group, acarbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, or a sulfamoyl group,

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein -HetAr- is a group containing aheteroaromatic ring group represented by the formula (III-1) or (III-2),and

in the formulas (III-1) and (III-2), Z1 and Z2 are each independentlyCRa or a nitrogen atom, and Z3 is an oxygen atom or a sulfur atom,

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein X is a lower alkylene groupoptionally having substituent(s) or a lower alkenylene group optionallyhaving substituent(s), and the substituent is selected from the groupconsisting of a halogeno group, a hydroxyl group, an amino group, alower alkyl group, a lower alkoxyl group, and a lower acyl group,

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein Y is a carbonyl group or a sulfonylgroup,

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein A is —OR5 (R5 is a hydrogen atom or alower alkyl group),

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein A is a group of the following formula(IV):

wherein R60 is a carboxyl group, a sulfo group, a phosphono group, alower alkoxycarbonyl group, or a hydroxyl group,

D is a lower alkylene group optionally having substituent(s), a loweralkenylene group optionally having substituent(s), or a lower alkynylenegroup optionally having substituent(s), wherein the substituent isselected from the group consisting of a nitro group, a halogeno group, acyano group, a hydroxyl group, a thiol group, an amino group, aguanidino group, a formyl group, a lower acyl group, a carboxyl group, asulfo group, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower acyloxy group, a loweracylamino group, a lower alkoxycarbonyl group, a carbamoyl group, alower alkylcarbamoyl group, a lower alkylsulfonylamino group, anarylsulfonylamino group optionally having substituent(s), a cycloalkylgroup optionally having substituent(s), an aryl group optionally havingsubstituent(s), an aryloxy group optionally having substituent(s), anarylthio group optionally having substituent(s), an aralkyl groupoptionally having substituent(s), an aralkyloxy group optionally havingsubstituent(s), an aralkylthio group optionally having substituent(s), aheterocyclic group optionally having substituent(s), a heterocyclic oxygroup optionally having substituent(s), a heterocyclic thio groupoptionally having substituent(s), and an oxo group, and

R70 is a hydrogen atom; a hydroxyl group, a lower alkyl group optionallyhaving substituent(s) or a lower alkoxyl group optionally havingsubstituent(s), or R70 and D may be bonded to form a cyclic amino groupoptionally having substituent(s),

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein

A is a group of the aforementioned formula (IV),

in the group of the formula (IV), R60 is a carboxyl group, a sulfogroup, a lower alkoxycarbonyl group, or a hydroxyl group,

D is a lower alkylene group optionally having substituent(s), whereinthe substituent is selected from the group consisting of a halogenogroup, a hydroxyl group, a thiol group, an amino group, a guanidinogroup, a carboxyl group, a sulfo group, a lower alkoxyl group, a loweralkylthio group, a lower alkylamino group, a lower acylamino group, alower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoylgroup, a lower alkylsulfonylamino group, an arylsulfonylamino groupoptionally having substituent(s), an aryl group optionally havingsubstituent(s), a heterocyclic group optionally having substituent(s),and an oxo group, and

R70 is a hydrogen atom, a hydroxyl group, a lower alkyl group optionallyhaving substituent(s), or a lower alkoxyl group optionally havingsubstituent(s), or R70 and D may be bonded to form a cyclic amino groupoptionally having substituent(s),

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I) wherein R1, R2, R3, and R4 are eachindependently a hydrogen atom, a nitro group, or a fluorine atom, and

HetAr is furan, thiophene, or thiazole each optionally havingsubstituent(s), or a pharmaceutically acceptable salt thereof.

The present invention also provides an intestinal serine proteaseinhibitor, comprising the above-mentioned heteroarylcarboxylic acidester derivative, or a pharmaceutically acceptable salt thereof as anactive ingredient.

The present invention also provides a dual inhibitor of trypsin andenteropeptidase, comprising the above-mentioned heteroarylcarboxylicacid ester derivative, or a pharmaceutically acceptable salt thereof asan active ingredient.

The present invention also provides a hyperglycemic inhibitor orhypoglycemic agent, comprising the above-mentioned heteroarylcarboxylicacid ester derivative, or a pharmaceutically acceptable salt thereof asan active ingredient.

The present invention also provides a prophylactic or therapeutic drugfor diabetes, comprising the above-mentioned heteroarylcarboxylic acidester derivative, or a pharmaceutically acceptable salt thereof as anactive ingredient.

The present invention also provides an insulin sensitizer comprising theabove-mentioned heteroarylcarboxylic acid ester derivative, or apharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a prophylactic or therapeutic drugfor obesity, hyperlipidemia, diabetic complication or metabolicsyndrome, comprising the above-mentioned heteroarylcarboxylic acid esterderivative, or a pharmaceutically acceptable salt thereof as an activeingredient.

The present invention also provides a method for preventing or treatingdiabetes, comprising administering an effective amount of theabove-mentioned heteroarylcarboxylic acid ester derivative, or apharmaceutically acceptable salt thereof.

The present invention also provides a method for improving insulinresistance, comprising administering an effective amount of theabove-mentioned heteroarylcarboxylic acid ester derivative, or apharmaceutically acceptable salt thereof.

The present invention also provides a method for preventing or treatingobesity, hyperlipidemia, diabetic complication or metabolic syndrome,comprising administering an effective amount of the above-mentionedheteroarylcarboxylic acid ester derivative, or a pharmaceuticallyacceptable salt thereof.

The present invention also provides use of the above-mentionedheteroarylcarboxylic acid ester derivative, or a pharmaceuticallyacceptable salt thereof for the prophylaxis or treatment of diabetes.

The present invention also provides use of the above-mentionedheteroarylcarboxylic acid ester derivative, or a pharmaceuticallyacceptable salt thereof for the improvement of insulin resistance.

The present invention also provides use of the above-mentionedheteroarylcarboxylic acid ester derivative, or a pharmaceuticallyacceptable salt thereof for the prophylaxis or treatment of obesity,hyperlipidemia, diabetic complication or metabolic syndrome.

The compound of the present invention has a blood glucose elevationsuppressing action and can be preferably used as a drug for thetreatment or prophylaxis of diabetes.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is explained in detail in the following.

In the present specification, the phrase “optionally havingsubstituent(s)” means “being substituted or unsubstituted”. Unlessotherwise specified, the position and number of the substituents may beany, and are not particularly limited. When substituted by two or moresubstituents, the substituents may be the same or different. Examples ofthe substituent include a nitro group, a halogeno group, a cyano group,a hydroxyl group, a thiol group, an amino group, a guanidino group, aformyl group, a phenyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a lower acyl group, a carboxyl group, asulfo group, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower alkoxycarbonyl group, acarbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a sulfamoyl group, and the like.

In the present specification, examples of the substituent of the“arylsulfonylamino group optionally having substituent(s)”, “cycloalkylgroup optionally having substituent(s)”, “aryl group optionally havingsubstituent(s)”, “aryloxy group optionally having substituent(s)”,“arylthio group optionally having substituent(s)”, “aralkyl groupoptionally having substituent(s)”, “aralkyloxy group optionally havingsubstituent(s)”, “aralkylthio group optionally having substituent(s)”,“heterocyclic group optionally having substituent(s)”, “heterocyclic oxygroup optionally having substituent(s)” and “heterocyclic thio groupoptionally having substituent(s)” include a nitro group, a halogenogroup, a cyano group, a hydroxyl group, a thiol group, an amino group, aguanidino group, a formyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a lower acyl group, a carboxyl group, asulfo group, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower alkoxycarbonyl group, acarbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a sulfamoyl group, and the like.

The “heteroaromatic ring” in the present specification is a 5- to10-membered aromatic ring optionally containing 1 to 3 hetero atoms suchas a nitrogen atom, an oxygen atom, a sulfur atom, and the like, andexamples thereof include a monocycle, and a fused aromatic ring whereintwo aromatic rings are fused. Examples of the monocycle include furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, oxadiazole, thiadiazole, pyridine, pyridazine,pyrimidine, pyrazine, and the like. Examples of the fused aromatic ringinclude indole, isoindole, benzofuran, benzothiophene, indolizine,quinoline, isoquinoline, purine, 1H-indazole, quinazoline, cinnoline,quinoxaline, phthalazine, pteridine, benzoxazole, benzothiazole,benzimidazole, and the like.

The “cyclic amino group” in the present specification is a saturated orunsaturated cyclic amino group having a carbon number of 2 to 7, whichmay contain one or more hetero atoms in the ring, such as a nitrogenatom, an oxygen atom, a sulfur atom, and the like. For example, apyrrolidinyl group, a pyrrolinyl group, a piperidinyl group, amorpholinyl group, a piperazinyl group, a thiomorpholinyl group, apiperidinonyl group, a piperazinonyl group and the like can bementioned.

The “lower alkyl group” is a straight chain or branched chain or cyclicalkyl group having a carbon number of 1 to 6. For example, a methylgroup, an ethyl group, an n-propyl group, an n-butyl group, an n-pentylgroup, an n-hexyl group, an isopropyl group, an isobutyl group, asec-butyl group, a tert-butyl group, an isopentyl group, a tert-pentylgroup, a neopentyl group, a 2-pentyl group, a 3-pentyl group, a 2-hexylgroup, a cyclopropyl group, a cyclopentyl group, and the like can bementioned.

The “lower alkenyl group” is a straight chain or branched chain alkenylgroup having a carbon number of 2 to 6, which includes each isomer. Forexample, a vinyl group, an allyl group, a propenyl group, a butenylgroup, a pentenyl group, a hexenyl group, and the like can be mentioned.

The “lower alkynyl group” is a straight chain or branched chain alkynylgroup having a carbon number of 2 to 6, which includes each isomer. Forexample, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a2-butynyl group, a 3-butynyl group, a pentynyl group, and the like canbe mentioned.

The “lower alkylene group” is a straight chain or branched chain orcyclic alkylene group having a carbon number of 1 to 6, with preferencegiven to a straight chain or a branched chain. For example, a methylenegroup, an ethylene group, an n-propylene group (—(CH₂)₃—), an n-butylenegroup (—(CH₂)₄—), an n-pentylene group (—(CH₂)₅—), an n-hexylene group(—(CH₂)₆—), an isopropylene group, an isobutylene group, an isopentylenegroup, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂CH₃)—,—CH₂—CH(CH₂CH₂CH₃)—CH₂—CH(CH₃)—CH₂CH₂—, —CH₂—CH(CH(CH₃)₂)—,—CH(CH₂CH₃)—, —CH(CH₃)—, —CH₂—C(CH₃)₂—, and the like can be mentioned.

The “lower alkenylene group” is a straight chain or branched chainalkenylene group having a carbon number of 2 to 6, which includes eachisomer. For example, a vinylene group, a 1-propenylene group, a2-propenylene group, a 2-butenylene group, a 3-butenylene group, apentenylene group, a hexenylene group, —CH═C(CH₃)—, and the like can bementioned.

The “lower alkynylene group” is a straight chain or branched chainalkynylene group having a carbon number of 2 to 6, which includes eachisomer. For example, an ethynylene group, a 1-propynylene group, a2-propynylene group, a 2-butynylene group, a 3-butynylene group, apentynylene group, and the like can be mentioned.

Examples of the “halogeno group” include a fluorine atom, a chlorineatom, a bromine atom, an iodine atom, and the like.

The “lower acyl group” is an acyl group having a straight chain orbranched chain or cyclic alkyl group or alkenyl group having a carbonnumber of 1 to 6. For example, an acetyl group, a propionyl group, abutyryl group, an isobutyryl group, a valeryl group, an isovalerylgroup, a pivaloyl group, a hexanoyl group, an acryloyl group, amethacryloyl group, a crotonoyl group, an isocrotonoyl group, acyclopropanoyl group, a cyclobutanoyl group, a cyclopentanoyl group, acyclohexanoyl group, and the like can be mentioned.

The “lower alkoxyl group” is an alkoxyl group having a straight chain orbranched chain or cyclic alkyl group having a carbon number of 1 to 6.For example, a methoxy group, an ethoxy group, an n-propoxy group, ann-butoxy group, an n-pentyloxy group, an n-hexyloxy group, an isopropoxygroup, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, acyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, anda cyclohexyloxy group can be mentioned.

The “lower alkylthio group” is an alkylthio group having a straightchain or branched chain or cyclic alkyl group having a carbon number of1 to 6. For example, a methylthio group, an ethylthio group, ann-propylthio group, an isopropylthio group, an n-butylthio group, anisobutylthio group, a sec-butylthio group, a tert-butylthio group, acyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group,a cyclobutylthio group, and the like can be mentioned.

The “lower alkylamino group” is an amino group mono- or di-substitutedby the aforementioned “lower alkyl group”. For example, a methylaminogroup, an ethylamino group, a propylamino group, an isopropylaminogroup, a dimethylamino group, a diethylamino group, a dipropylaminogroup, a diisopropylamino group, an ethylmethylamino group, and the likecan be mentioned.

The “lower acyloxy group” is a group wherein an oxygen atom is bonded tothe carbon of the carbonyl moiety of the aforementioned “lower acylgroup”. For example, an acetyloxy group, a propionyloxy group, abutyryloxy group, an isobutyryloxy group, a valeryloxy group, anisovaleryloxy group, a pivaloyloxy group, a hexanoyloxy group, anacryloyloxy group, a methacryloyloxy group, a crotonoyloxy group, anisocrotonoyloxy group, and the like can be mentioned.

The “lower acylamino group” is a group wherein a nitrogen atom is bondedto the carbon of the carbonyl moiety of the aforementioned “lower acylgroup”. For example, an acetylamino group, a propionylamino group, abutyrylamino group, an isobutyrylamino group, a valerylamino group, anisovalerylamino group, a pivaloylamino group, a hexanoylamino group, anacryloylamino group, a methacryloylamino group, a crotonoylamino group,an isocrotonoylamino group, and the like can be mentioned.

The “lower alkoxycarbonyl group” is a carbonyl group having theaforementioned “lower alkoxyl group”. For example, a methoxycarbonylgroup, an ethoxycarbonyl group, a propoxycarbonyl group, anisopropoxycarbonyl group, an n-butoxycarbonyl group, anisobutoxycarbonyl group, a sec-butoxycarbonyl group, atert-butoxycarbonyl group, and the like can be mentioned.

The “lower alkylcarbamoyl group” is a group wherein a nitrogen atom ofthe aforementioned “lower alkylamino group” or “cyclic amino group”, anda carbon atom of the carbonyl group are bonded. For example, anN-methylcarbamoyl group, an N-ethylcarbamoyl group, anN,N-dimethylcarbamoyl group, a 1-pyrrolidinylcarbonyl group, a1-piperidinylcarbonyl group, a 4-morpholinylcarbonyl group, and the likecan be mentioned.

The “lower alkylsulfonylamino group” is a group wherein a nitrogen atomis bonded to a sulfonyl group wherein the aforementioned “lower alkylgroup” is bonded to a sulfur atom. For example, a methylsulfonylaminogroup, an ethylsulfonylamino group, a propylsulfonylamino group, anisopropylsulfonylamino group, a butylsulfonylamino group, anisobutylsulfonylamino group, and the like can be mentioned.

The “arylsulfonylamino group” is a group wherein a nitrogen atom isbonded to a sulfur atom of a sulfonyl group substituted by an arylgroup. For example, a phenylsulfonylamino group, a naphthylsulfonylaminogroup, and the like can be mentioned.

Examples of the “aryl group” include an aryl group having a carbonnumber of 6 to 14 such as a phenyl group, a naphthyl group, and thelike.

The “heterocyclic group” is a 5- to 14-membered monocyclic to tricyclicheterocyclic group containing, as a ring atom, 1 to 4 hetero atomsselected from an oxygen atom, a sulfur atom, and a nitrogen atom. Anycarbon atom as a ring atom may be substituted by an oxo group, and asulfur atom or a nitrogen atom may be oxidized to form an oxide. Inaddition, it may be condensed with a benzene ring. For example, apyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinylgroup, a furyl group, a thienyl group, a pyrrolyl group, an isoxazolylgroup, an oxazolyl group, an isothiazolyl group, a thiazolyl group, apyrazolyl group, an imidazolyl group, an oxadiazolyl group, athiadiazolyl group, a triazolyl group, a tetrazolyl group, abenzofuranyl group, a benzothienyl group, an indolyl group, anisoindolyl group, a benzoxazolyl group (=a benzooxazolyl group), abenzothiazolyl group, a benzimidazolyl group (=a benzoimidazolyl group),an indazolyl group, a benzisoxazolyl group, a benzisothiazolyl group, abenzofurazanyl group, a benzothiadiazolyl group, a purinyl group, aquinolinyl group, an isoquinolyl group, a cinnolinyl group, aphthalazinyl group, a quinazolinyl group, a quinoxalinyl group, apteridinyl group, an imidazooxazolyl group, an imidazothiazolyl group,an imidazoimidazolyl group, a dibenzofuranyl group, a dibenzothienylgroup, a carbazolyl group, an acridinyl group, a pyrrolidinyl group, apyrazolidinyl group, an imidazolidinyl group, a pyrrolinyl group, apyrazolinyl group, an imidazolinyl group, a tetrahydrofuranyl group, atetrahydrothiophenyl group, a thiazolidinyl group, a piperidinyl group,a piperazinyl group, a quinuclidinyl group, a tetrahydropyranyl group, atetrahydrothiopyranyl group, a morpholinyl group, a thiomorpholinylgroup, a dioxolanyl group, a homopiperidinyl group, a homopiperazinylgroup, an indolinyl group, an isoindolinyl group, a chromanyl group, anisochromanyl group, a tetrahydronaphthyridinyl group, an azaindolylgroup, and the like can be mentioned. Preferably, a thiadiazolyl group,an imidazolyl group, a tetrazolyl group, a piperidinyl group, apiperazinyl group, a thiazolidinyl group, and the like can be mentioned.

As the “phenylene group”, a 1,4-phenylene group, a 1,3-phenylene group,and the like can be mentioned.

The “thiophenylene group” is divalent thiophene. For example, athiophene-2,5-diyl group and the like can be mentioned.

The “serine protease” in the present specification is a protease having,as a catalytic residue, a serine residue having nucleophilicity. Forexample, trypsin, chymotrypsin, elastase, enteropeptidase, kallikrein,thrombin, factor Xa, and tryptase, and the like can be mentioned. Inaddition, the “serine protease inhibition” in the present specificationmeans decrease or disappearance of the aforementioned serine proteaseactivity. Preferably, it is an inhibition of the activity of intestinalserine proteases such as trypsin, enteropeptidase, chymotrypsin,elastase and the like, particularly preferably inhibition of trypsin andenteropeptidase activities.

The serine protease inhibitor of the present invention is a dualinhibitor that simultaneously inhibits at least trypsin andenteropeptidase.

The diabetes in the present specification means type I diabetes mellitusand type II diabetes mellitus, with preference given to type II diabetesmellitus.

In the present invention, the heteroarylcarboxylic acid ester derivativerepresented by formula (I) or a pharmaceutically acceptable salt thereofis preferably as follows.

In formula (I), preferably, R1, R2, R3, and R4 are each independently ahydrogen atom, a nitro group, a halogeno group, and the like, morepreferably a hydrogen atom, a nitro group, a fluorine atom, a chlorineatom, a bromine atom, and the like, particularly extremely preferably ahydrogen atom, a fluorine atom, and the like.

In formula (I), the group represented by HetAr is preferably a 5- to10-membered aromatic ring containing 1 to 3 hetero atoms, whichoptionally has substituent(s), and furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, benzofuran, benzothiophene, benzoxazole,benzothiazole, and the like can be mentioned. A 5-membered heteroarylring is more preferable, and furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, and the like can be mentioned, and particularlypreferably, furan, thiophene, thiazole, and the like can be mentioned.

Here, as the hetero atom, an oxygen atom, a sulfur atom, a nitrogenatom, and the like can be mentioned.

In addition, when a group represented by HetAr has a substituent,examples of the substituent include a nitro group, a halogeno group, acyano group, a hydroxyl group, a thiol group, an amino group, aguanidino group, a formyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a lower acyl group, a carboxyl group, asulfo group, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower acyloxy group, a loweracylamino group, a lower alkoxycarbonyl group, a carbamoyl group, alower alkylcarbamoyl group, a lower alkylsulfonylamino group, asulfamoyl group, and the like. Preferably, a halogeno group, a hydroxylgroup, an amino group, a lower alkyl group, a lower alkenyl group, alower alkynyl group, a lower acyl group, a carboxyl group, a sulfogroup, a phosphono group, a lower alkoxyl group, a lower alkylaminogroup, a lower alkoxycarbonyl group, a carbamoyl group, a loweralkylcarbamoyl group, a lower alkylsulfonylamino group, a sulfamoylgroup, and the like can be mentioned. More preferably, a halogeno group,a hydroxyl group, an amino group, a lower alkyl group, a lower alkoxylgroup, a lower alkylamino group, and the like can be mentioned. Thenumber of the substituents is preferably 1 to 3, more preferably 1 or 2,further preferably 1. In addition, the group represented by HetAr ispreferably unsubstituted.

A group represented by HetAr is preferably a group of the followingformula (III-1) or (III-2).

wherein Z1 and Z2 are each independently CRa or a nitrogen atom, and Z3is an oxygen atom, a sulfur atom or NRb, wherein Ra and Rb may be thesame or different, and are each independently selected from a hydrogenatom, a nitro group, a halogeno group, a cyano group, a hydroxyl group,a thiol group, an amino group, a guanidino group, a formyl group, alower alkyl group, a lower alkenyl group, a lower alkynyl group, a loweracyl group, a carboxyl group, a sulfo group, a phosphono group, a loweralkoxyl group, a lower alkylthio group, a lower alkylamino group, alower acyloxy group, a lower acylamino group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, and a sulfamoyl group.

In groups of the formulas (III-1) and (III-2), Z1 is preferably CH or anitrogen atom, and CH is particularly preferable.

In groups of the formulas (III-1) and (III-2), Z2 is preferably CH.

In groups of the formulas (III-1) and (III-2), Z3 is preferably anoxygen atom or a sulfur atom.

In groups of the formulas (III-1) and (III-2), preferably, Ra and Rb areeach independently a hydrogen atom, a halogeno group, a hydroxyl group,an amino group, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a lower acyl group, a carboxyl group, a sulfo group, aphosphono group, a lower alkoxyl group, a lower alkylamino group, alower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoylgroup, a lower alkylsulfonylamino group, a sulfamoyl group, and thelike, and a hydrogen atom, a halogeno group, a hydroxyl group, an aminogroup, a lower alkyl group, a lower alkoxyl group, a lower alkylaminogroup, and the like are more preferable.

In the formula (I), X is preferably a straight chain or branched chainlower alkylene group having a carbon number of 1 to 6 or a straightchain or branched chain lower alkenylene group having a carbon number of2 to 4, and a straight chain or branched chain lower alkylene grouphaving a carbon number of 1 to 5 is more preferable.

When X is a phenylene group or a thiophenylene group, it is anunsubstituted phenylene group or an unsubstituted thiophenylene group.

In the formula (I), when a group represented by X has a substituent,examples of the substituent include a nitro group, a halogeno group, acyano group, a hydroxyl group, a thiol group, an amino group, a loweralkyl group, a guanidino group, a formyl group, a lower acyl group, acarboxyl group, a sulfo group, a phosphono group, a lower alkoxyl group,a lower alkylthio group, a lower alkylamino group, a lower acyloxygroup, a lower acylamino group, a lower alkoxycarbonyl group, acarbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a sulfamoyl group, and the like, and ahalogeno group, a hydroxyl group, an amino group, a lower alkyl group, alower acyl group, a carboxyl group, a sulfo group, a phosphono group, alower alkoxyl group, a lower alkylthio group, a lower alkylamino group,a lower acyloxy group, a lower acylamino group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a sulfamoyl group, and the like arepreferable. The number of the substituents is preferably 1 to 3, morepreferably 1 or 2, further preferably 1. In addition, the grouprepresented by X is preferably unsubstituted.

In the formula (I), Y is preferably a carbonyl group.

In the formula (I), A is preferably a group represented by —OR5, a groupof the following formula (II), a group of the following formula (IV),—U—CH(R6′)R7′ or —NH—N(R6″)R7″.

In addition, in the formula (I), A is preferably a group represented by—OR5, a group of the following formula (II) or a group of the followingformula (IV). Among these, a group represented by the following formula(IV) is particularly preferable.

When the group represented by A is —OR5, preferred as R5 is a hydrogenatom.

In a group of formula (II), preferably, R6 and R7 are each independentlya hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxylgroup, and the like, and a hydrogen atom, a lower alkyl group having acarbon number of 1 to 3, or the like is particularly preferable.

Here, when a group represented by R6 or R7 has a substituent, examplesof the substituent include a nitro group, a halogeno group, a cyanogroup, a hydroxyl group, a thiol group, an amino group, a guanidinogroup, a formyl group, a lower acyl group, a carboxyl group, a sulfogroup, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower acyloxy group, a loweracylamino group, a lower alkoxycarbonyl group, a carbamoyl group, alower alkylcarbamoyl group, a lower alkylsulfonylamino group, anarylsulfonylamino group optionally having substituent(s), a cycloalkylgroup optionally having substituent(s), an aryl group optionally havingsubstituent(s), an aryloxy group optionally having substituent(s), anarylthio group optionally having substituent(s), an aralkyl groupoptionally having substituent(s), an aralkyloxy group optionally havingsubstituent(s), an aralkylthio group optionally having substituent(s), aheterocyclic group optionally having substituent(s), a heterocyclic oxygroup optionally having substituent(s), a heterocyclic thio groupoptionally having substituent(s), an oxo group, and the like. A halogenogroup, a hydroxyl group, a carboxyl group, a sulfo group, a phosphonogroup, a lower alkoxycarbonyl group, an aryl group optionally havingsubstituent(s), a heterocyclic group optionally having substituent(s),an oxo group, and the like are preferable, and a hydroxyl group, acarboxyl group, a sulfo group, a lower alkoxycarbonyl group, and thelike are particularly preferable. The number of the substituents ispreferably 1 to 3, more preferably 1 or 2.

As a cyclic amino group formed by R6 and R7 bonded to each other, apyrrolidinyl group, a piperidinyl group, and the like are preferable.

When the cyclic amino group formed by R6 and R7 bonded to each other hasa substituent, examples of the substituent include a nitro group, ahalogeno group, a cyano group, a hydroxyl group, a thiol group, an aminogroup, a guanidino group, a formyl group, a lower alkyl group, a loweralkenyl group, a lower alkynyl group, a lower acyl group, a carboxylgroup, a sulfo group, a phosphono group, a lower alkoxyl group, a loweralkylthio group, a lower alkylamino group, a lower alkoxycarbonyl group,a carbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a sulfamoyl group, an oxo group, and the like.A hydroxyl group, a carboxyl group, a sulfo group, a phosphono group, alower alkoxycarbonyl group, and the like are preferable. The number ofthe substituents is preferably 1 to 3, more preferably 1 or 2.

In a group of formula (IV), R60 is preferably a carboxyl group or asulfo group, and a carboxyl group is particularly preferable.

In a group of formula (IV), D is preferably a lower alkylene groupoptionally having substituent(s), and a lower alkylene group having acarbon number of 1 to 3 is particularly preferable.

In a group of formula (IV), when a group represented by D has asubstituent, preferable examples of the substituent include a halogenogroup, a hydroxyl group, a carboxyl group, a sulfo group, a phosphonogroup, a lower alkoxycarbonyl group, an aryl group optionally havingsubstituent(s), a heterocyclic group optionally having substituent(s),an oxo group, and the like, and, a hydroxyl group, a carboxyl group, asulfo group, a lower alkoxycarbonyl group, and the like are particularlypreferable. The number of the substituents is preferably 1 to 3, morepreferably 1 or 2, further preferably 1. In addition, the grouprepresented by D is preferably unsubstituted.

In a group of the formula (IV), R70 is preferably a hydrogen atom, alower alkyl group having a carbon number of 1 to 3, a lower alkoxylgroup having a carbon number of 1 to 2, or the like, and a hydrogenatom, a lower alkyl group having a carbon number of 1 to 3, and the likeare particularly preferable.

In a group of formula (IV), when the group represented by R70 has asubstituent, examples of the substituent include a nitro group, ahalogeno group, a cyano group, a hydroxyl group, a thiol group, an aminogroup, a guanidino group, a formyl group, a lower acyl group, a carboxylgroup, a sulfo group, a phosphono group, a lower alkoxyl group, a loweralkylthio group, a lower alkylamino group, a lower acyloxy group, alower acylamino group, a lower alkoxycarbonyl group, a carbamoyl group,a lower alkylcarbamoyl group, a lower alkylsulfonylamino group, anarylsulfonylamino group optionally having substituent(s), a cycloalkylgroup optionally having substituent(s), an aryl group optionally havingsubstituent(s), an aryloxy group optionally having substituent(s), anarylthio group optionally having substituent(s), an aralkyl groupoptionally having substituent(s), an aralkyloxy group optionally havingsubstituent(s), an aralkylthio group optionally having substituent(s), aheterocyclic group optionally having substituent(s), a heterocyclic oxygroup optionally having substituent(s), a heterocyclic thio groupoptionally having substituent(s), an oxo group. and the like. A halogenogroup, a hydroxyl group, a carboxyl group, a sulfo group, a phosphonogroup, a lower alkoxycarbonyl group, an aryl group optionally havingsubstituent(s), a heterocyclic group optionally having substituent(s),an oxo group, and the like are preferable, and a hydroxyl group, acarboxyl group, a sulfo group, and a lower alkoxycarbonyl group areparticularly preferable. The number of the substituents is preferably 1to 3, more preferably 1 or 2, further preferably 1.

As the cyclic amino group formed by R70 and D bonded to each other, apyrrolidinyl group, a piperidinyl group, and the like are preferable.

When the cyclic amino group formed by R70 and D bonded to each other hasa substituent, examples of the substituent include a nitro group, ahalogeno group, a cyano group, a hydroxyl group, a thiol group, an aminogroup, a guanidino group, a formyl group, a lower alkyl group, a loweralkenyl group, a lower alkynyl group, a lower acyl group, a carboxylgroup, a sulfo group, a phosphono group, a lower alkoxyl group, a loweralkylthio group, a lower alkylamino group, a lower alkoxycarbonyl group,a carbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a sulfamoyl group, an oxo group, and the like,and a hydroxyl group, a carboxyl group, a sulfo group, a phosphonogroup, a lower alkoxycarbonyl group, and the like are preferable. Thenumber of the substituents is preferably 1 to 3, more preferably 1 or 2,further preferably 1.

A heteroarylcarboxylic acid ester derivative wherein, in a group of theformula (IV), R60 is a carboxyl group, D is a lower alkylene groupoptionally having a carboxyl group, and R70 is a lower alkyl groupoptionally having a carboxyl group or a hydrogen atom, or apharmaceutically acceptable salt thereof is particularly preferable.

A heteroarylcarboxylic acid ester derivative represented by any of thefollowing formulas or a pharmaceutically acceptable salt thereof ispreferable.

A heteroarylcarboxylic acid ester derivative represented by any of thefollowing formulas or a pharmaceutically acceptable salt thereof is alsopreferable.

As preferable embodiments of the heteroarylcarboxylic acid esterderivative represented by the formula (I) or a pharmaceuticallyacceptable salt thereof, the following can also be mentioned.

Compound a

A compound represented by the formula (I) wherein R1 is a hydrogen atom,a nitro group, a halogeno group, or a straight chain or branched chainalkoxyl group having a carbon number of 1 to 6;

R3 is a hydrogen atom or a halogeno group;R2 and R4 are hydrogen atoms;HetAr is furan, thiophene, or thiazole each optionally having 1 or 2substituents selected from a straight chain or branched chain alkylgroup having a carbon number of 1 to 6;

X is

(1) a straight chain or branched chain alkylene group having a carbonnumber of 1 to 6, which optionally has a carboxyl group,

(2) a straight chain or branched chain alkenylene group having a carbonnumber of 2 to 6,

(3) a phenylene group, or

(4) a thiophenylene group;

Y is a carbonyl group or a sulfonyl group; andA is —OR5 (R5 is a hydrogen atom);

a group of the following formula (II):

wherein R6 is a straight chain or branched chain alkyl group having acarbon number of 1 to 6, which optionally has 1 or 2 substituentsselected from the group consisting of an aryl group having a carbonnumber of 6 to 14 and optionally having a hydroxyl group, a hydroxylgroup, a carboxyl group, sulfo group, a phosphono group, an amino groupmono- or di-substituted by a straight chain or branched chain alkylgroup having a carbon number of 1 to 6 and a carbamoyl group and

R7 is

-   -   (1) a hydrogen atom,    -   (2) a straight chain or branched chain alkyl group having a        carbon number of 1 to 6 and optionally having 1 or 2        substituents selected from the group consisting of an aryl group        having a carbon number of 6 to 14, a hydroxyl group, and a        carboxyl group, or    -   (3) a straight chain or branched chain alkenyl group having a        carbon number of 2 to 6, or

R6 and R7 are optionally bonded to form a pyrrolidinyl group or apiperidinyl group, each of which optionally has 1 or 2 substituentsselected from the group consisting of a hydroxyl group and a carboxylgroup;

a group of the following formula (II-2):

—U—CH(R6′)R7′  (II-2)

wherein U is O or S, and R6′ and R7′ may be the same or different andare each independently a straight chain or branched chain alkyl grouphaving a carbon number of 1 to 6 and optionally having a carboxyl group,or a carboxyl group; or

a group of the following formula (II-3):

—NH—N(R6″)R7″  (II-3)

wherein R6″ and R7″ may be the same or different and are eachindependently a straight chain or branched chain alkyl group having acarbon number of 1 to 6 and optionally having a carboxyl group,

or a pharmaceutically acceptable salt thereof.

Compound b.

A compound represented by the formula (I) wherein R1 is a hydrogen atom,a nitro group, a halogeno group or a straight chain or branched chainalkoxyl group having a carbon number of 1 to 6;

R3 is a hydrogen atom or a halogeno group;

R2 and R4 are hydrogen atoms;

HetAr is furan, thiophene, or thiazole each optionally having 1 or 2substituents selected from a straight chain or branched chain alkylgroup having a carbon number of 1 to 6;

X is

(1) a straight chain or branched chain alkylene group having a carbonnumber of 1 to 6 and optionally having a carboxyl group,

(2) a straight chain or branched chain alkenylene group having a carbonnumber of 2 to 6,

(3) a phenylene group, or

(4) a thiophenylene group;

Y is a carbonyl group or a sulfonyl group, andA is —OR5 (R5 is a hydrogen atom),

a group of the following formula (II):

wherein R6 is a straight chain or branched chain alkyl group having acarbon number of 1 to 6 and having 1 or 2 substituents selected from thegroup consisting of an aryl group having a carbon number of 6 to 14 andoptionally having a hydroxyl group, a hydroxyl group, a carboxyl group,a sulfo group, a phosphono group, an amino group mono- or di-substitutedby a straight chain or branched chain alkyl group having a carbon numberof 1 to 6, and a carbamoyl group, and

R7 is

-   -   (1) a hydrogen atom,    -   (2) a straight chain or branched chain alkyl group having a        carbon number of 1 to 6 and optionally having 1 or 2        substituents selected from the group consisting of an aryl group        having a carbon number of 6 to 14, a hydroxyl group and a        carboxyl group, or    -   (3) a straight chain or branched chain alkenyl group having a        carbon number of 2 to 6, or

R6 and R7 are optionally bonded to form a pyrrolidinyl group or apiperidinyl group each having 1 or 2 substituents selected from thegroup consisting of a hydroxyl group and a carboxyl group, a group ofthe following formula (II-2):

—U—CH(R6′)R7′  (II-2)

wherein U is O or S, and R6′ and R7′ may be the same or different andare each independently a straight chain or branched chain alkyl grouphaving a carbon number of 1 to 6 and having a carboxyl group or acarboxyl group, or a group of the following formula (II-3):

—NH—N(R6″)R7″  (II-3)

wherein R6″ and R7″ may be the same or different and are eachindependently a straight chain or branched chain alkyl group having acarbon number of 1 to 6 and having a carboxyl group,

or a pharmaceutically acceptable salt thereof.

Compound c.

A compound represented by the formula (I) wherein R1 is a hydrogen atom,a nitro group, a halogeno group, or a straight chain or branched chainalkoxyl group having a carbon number of 1-6;

R3 is a hydrogen atom or a halogeno group;R2 and R4 are hydrogen atoms;HetAr is furan, thiophene or thiazole each optionally having 1 or 2substituents selected from a straight chain or branched chain alkylgroup having a carbon number of 1 to 6, X is

(1) a straight chain or branched chain alkylene group having a carbonnumber of 1 to 6 and optionally having a carboxyl group,

(2) a straight chain or branched chain alkenylene group having a carbonnumber of 2 to 6,

(3) a phenylene group, or

(4) a thiophenylene group;

Y is a carbonyl group or a sulfonyl group; andA is —OR5 (R5 is a hydrogen atom) or

a group of the following formula (IV):

wherein R60 is a carboxyl group, a sulfo group, a phosphono group, or ahydroxyl group,

D is a straight chain or branched chain alkylene group having a carbonnumber of 1 to 6 and optionally having substituent(s), and thesubstituent is selected from the group consisting of an aryl grouphaving a carbon number of 6 to 14 and optionally having a hydroxylgroup, a hydroxyl group, a carboxyl group, a sulfo group, and acarbamoyl group, and

R70 is

-   -   (1) a hydrogen atom,    -   (2) a straight chain or branched chain alkyl group having a        carbon number of 1 to 6 and optionally having 1 or 2        substituents selected from the group consisting of an aryl group        having a carbon number of 6 to 14, a hydroxyl group, and a        carboxyl group, or    -   (3) a straight chain or branched chain alkenyl group having a        carbon number of 2 to 6, or

R70 and D are optionally bonded to form a pyrrolidinyl group or apiperidinyl group each optionally having 1 or 2 substituents selectedfrom the group consisting of a hydroxyl group and a carboxyl group,

or a pharmaceutically acceptable salt thereof.

As the serine protease inhibitory activity, an activity ofsimultaneously inhibiting trypsin and enteropeptidase is preferable.

When the compound of the present invention can form a salt, apharmaceutically acceptable salt is preferable. Examples of suchpharmaceutically acceptable salts for a compound having an acidic groupsuch as a carboxyl group and the like include an ammonium salt, saltswith alkali metals such as sodium, potassium, and the like, salts withalkaline earth metals such as calcium, magnesium, and the like, analuminum salt, a zinc salt, salts with an organic amines such astriethylamine, ethanolamine, morpholine, pyrrolidine, piperidine,piperazine, dicyclohexylamine, and the like, and salts with a basicamino acid such as arginine, lysine, and the like. Examples of suchpharmaceutically acceptable salts for a compound having a basic groupinclude salts with an inorganic acid such as hydrochloric acid, sulfuricacid, phosphoric acid, nitric acid, hydrobromic acid, and the like,salts with an organic carboxylic acid such as acetic acid, citric acid,benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid,tannic acid, butyric acid, hibenzic acid (2-(4-hydroxybenzoyl)benzoicacid), pamoic acid, enanthic acid, decanoic acid, teoclic acid,salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid, andthe like, and salts with an organic sulfonic acid such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, andthe like.

The compound of the present invention also encompasses all opticalisomers, stereoisomers, tautomers, rotamers, and mixtures thereof atoptional ratios. These can be obtained each as a single productaccording to a synthesis method and separation method known per se. Forexample, an optical isomer can be obtained by using an optically activesynthesis intermediate or by optically resolving a racemate of asynthesis intermediate or final product by a conventional method.

The compound of the present invention also includes solvates of thecompound such as hydrates, alcohol adducts, and the like.

The compound of the present invention may be converted to a prodrug. Theprodrug of the present invention means a compound that is converted inthe body to produce the compound of the present invention. For example,when an active form contains a carboxyl group or a phosphoric acidgroup, an ester thereof, amide thereof, and the like can be mentioned.When an active form contains a carboxyl group, a group to be convertedto a carboxyl group by oxidative metabolism, such as a hydroxymethylgroup and the like can be mentioned. In addition, when the active formcontains an amino group, examples thereof include amide thereof, acarbamate thereof and the like. When the active form contains a hydroxylgroup, examples thereof include esters thereof, carbonates thereof,carbamates thereof, and the like. When the compound of the presentinvention is converted to a prodrug, it may be bonded to amino acid orsaccharide.

The present invention also encompasses a metabolite of the compound ofthe present invention. The metabolite of the compound of presentinvention means a compound resulting from the conversion of the compoundof the present invention by a metabolic enzyme and the like in the body.For example, a compound wherein a hydroxyl group is introduced on thebenzene ring of the compound of the present invention due to themetabolism, a compound wherein glucuronic acid, glucose, or an aminoacid is bonded to the carboxylic acid moiety of the compound of thepresent invention or a hydroxyl group is added by the metabolism, andthe like can be mentioned.

The compound of the present invention and a pharmaceutically acceptablesalt thereof have a superior blood glucose elevation suppressing actionfor mammals such as humans, bovines, horses, dogs, mice, rats, and thelike, and can be used as a medicament, which is administered as it is oras a pharmaceutical composition containing the same mixed with apharmaceutically acceptable carrier according to a method known per se.While oral administration is generally preferable, parenteraladministration can also be employed (e.g., routes such as intravenous,subcutaneous, intramuscular, suppository, enema, ointment, patch,sublingual, eye drop, inhalation administrations, and the like). Whilethe dose used for the above-mentioned objects is determined according tothe desired treatment effect, administration method, duration oftreatment, age, body weight, and the like, a daily dose of 1 μg to 10 gfor oral administration and 0.01 μg to 1 g, preferably 0.1 μg to 1 g,for parenteral administration is used, which is generally administeredto an adult by an oral or parenteral route in one to several portionsper day. In addition, the content of the compound of the presentinvention in the above-mentioned pharmaceutical composition is about0.01 wt % to 100 wt % of the whole composition.

Examples of the pharmaceutically acceptable carrier for thepharmaceutical composition of the present invention include variousorganic or inorganic carrier substances conventionally used aspreparation materials. For example, an excipient, lubricant, binder,disintegrant, water-soluble polymer, and basic inorganic salt in a solidpreparation; a solvent, solubilizing agents, suspending agent,isotonicity agent, buffering agent, and soothing agent in a liquidpreparation, and the like can be mentioned. Where necessary, generaladditives such as a preservative, antioxidant, colorant, sweeteningagent, souring agent, effervescing agent, flavor, and the like can alsobe used.

The dosage form of such pharmaceutical composition may be a tablet,powder, pill, granule, capsule, suppository, solution, sugar-coatedagent, depot, syrup, suspension, emulsion, troche, sublingual agent,adhesive preparation, oral disintegrant (tablet), inhalant, enema,ointment, patch, tape, or eye drop, and these can be produced usingconventional formulation auxiliaries and according to a conventionalmethod.

The pharmaceutical composition of the present invention can be producedaccording to a method conventionally used in the technical field ofpharmaceutical formulation, for example, the method described in theJapanese Pharmacopoeia and the like. Specific production methods of thepreparation are explained in detail in the following.

For example, when the compound of the present invention is prepared asan oral preparation, a excipient and, where necessary, a binder,disintegrant, lubricant, colorant, flavoring agent, and the like arefurther added, and the mixture is processed to give, for example, atablet, powder, pill, granule, capsule, suppository, solution,sugar-coated agent, depot, syrup, and the like according to aconventional method. Examples of the excipient include lactose,cornstarch, sucrose, glucose, sorbitol, crystalline cellulose, and thelike. Examples of the binder include polyvinyl alcohol, polyvinyl ether,ethylcellulose, methylcellulose, gum arabic, tragacanth, gelatin,shellac, hydroxypropylcellulose, hydroxypropylstarch,polyvinylpyrrolidone, and the like. Examples of the disintegrant includestarch, agar, gelatin powder, crystalline cellulose, calcium carbonate,sodium hydrogen carbonate, calcium citrate, dextran, pectin, and thelike. Examples of the lubricant include magnesium stearate, talc,polyethylene glycol, silica, hydrogenated vegetable oil, and the like.As the colorant, one acceptable to add to a pharmaceutical product isused, and as the flavoring agent, cocoa powder, menthol, aromatic acid,peppermint oil, borneol, powdered cinnamon bark, and the like are used.Where necessary, these tablets and granules are applied with a coatingas appropriate such as sugar coating, gelatin coating, and the like.

When an injection is to be prepared, a pH adjuster, buffering agent,stabilizer, preservative, and the like are added where necessary, andthe mixture is processed to give subcutaneous, intramuscular, orintravenous injection according to a conventional method.

While the compound of the present invention can be used as an agent forthe treatment or prophylaxis of diabetes as mentioned above, it can alsobe used in combination with other therapeutic agents for diabetes andagents for the treatment or prophylaxis of diabetic complications, whichare used generally. Examples of the therapeutic agents for diabetes andagents for the treatment or prophylaxis of diabetic complications, whichare used generally, include combinations and mixtures of one or morekinds of insulin preparation, insulin derivative, insulin-like agent,insulin secretagogue, insulin sensitizer, biguanide, gluconeogenesisinhibitor, glucose absorption inhibitor, renal glucose reabsorptioninhibitor, β3 adrenoceptor agonist, glucagon-like peptide-1 (7-37),glucagon-like peptide-1 (7-37) analogs, glucagon-like peptide-1 receptoragonist, dipeptidyl peptidase IV inhibitor, aldose reductase inhibitor,inhibitor of advanced glycation end product formation, glycogen synthasekinase-3 inhibitor, glycogen phosphorylase inhibitor, antihyperlipidemicdrug, anorectic agent, lipase inhibitor, antihypertensive agent,peripheral circulation improving agent, antioxidant, a therapeutic drugfor diabetic neuropathy, and the like.

A medicament to be used in combination with the compound of the presentinvention may be mixed to give a single agent or each may be formulatedinto separate preparations, or prepared into a combination preparation(set, kit, pack) obtained by packaging each of the separately formulatedpreparations in one container.

The administration form of combined use is not particularly limited and,for example, (1) administration as a single preparation, (2)simultaneous administration of separate preparations by the sameadministration route, (3) administration of separate preparations in astaggered manner by the same administration route, (4) simultaneousadministration of separate preparations by different administrationroutes, (5) administration of separate preparations in a staggeredmanner by different administration routes, and the like can bementioned.

In addition, the compound of the present invention is also useful evenwhen contained in food.

A food composition containing the compound of the present invention isuseful as a food for the treatment or prophylaxis of diabetes.

The “food” of the present invention means general foods, which includefood for specified health uses and food with nutrient function claimsdefined by Food with Health Claims of Consumer Affairs Agency,Government of Japan, in addition to general foods including so-calledhealth food, and further encompasses dietary supplements.

The form of the food composition of the present invention is notparticularly limited, and the composition may take any form as long asit can be orally ingested.

Examples thereof include powder, granule, tablet, hard capsules, softcapsule, liquid (drinks, jelly drinks, and the like), candy, chocolate,and the like, all of which can be produced according to a method knownper se in the technical field.

The content of the compound of the present invention in the foodcomposition is appropriately determined to afford an appropriate dosewithin the indicated range.

The food composition of the present invention can use other foodadditives as necessary. Examples of such food additives include thosegenerally used as components of health foods such as a fruit juice,dextrin, cyclic oligosaccharide, saccharides (monosaccharides such asfructose, glucose, and the like, and polysaccharides), acidulant,flavor, powdered green tea, and the like, which are used for controllingand improving taste, emulsifier, collagen, whole milk powder,polysaccharide thickener, agar, and the like, which are used forimproving texture, and further, vitamins, eggshell calcium, calciumpantothenate, the other minerals, royal jelly, propolis, honey, dietaryfiber, Agaricus, chitin, chitosan, flavonoids, carotenoids, lutein,traditional Japanese herbal medicine, chondroitin, various amino acids,and the like.

A production method of a representative compound from theheteroarylcarboxylic acid ester derivatives represented by the formula(I), which is the compound of the present invention, is shown below.

Heteroarylcarboxylic acid ester derivative (F) represented by theformula (I) wherein X is a lower alkylene group or a lower alkenylenegroup, A is —OR5, and R5 is a lower alkyl group can be produced asfollows.

Alkenylene derivative (C) can be synthesized by reacting aldehyde (A)(wherein E₁ is a protecting group such as a methyl group, an ethylgroup, a tert-butyl group, a benzyl group, and the like) with Wittigreagent (B) (wherein X′ is X or a group capable of chemically convertingto X together with methyne between HetAr and X′ in (C)) in, for example,a solvent that does not adversely influence the reaction, such astetrahydrofuran and the like, in the presence of, for example, a basesuch as sodium hydride and the like. Alkenylene derivative (C) can beconverted to carboxylic acid derivative (D) by deprotection such ashydrolysis and the like in, for example, a solvent that does notadversely influence the reaction, such as tetrahydrofuran, methanol, andthe like, by using, for example, a base such as sodium hydroxide and thelike. Objective heteroarylcarboxylic acid ester derivative (F) wherein Xis a lower alkenylene group can be produced by esterifying carboxylicacid derivative (D) with amidinophenol derivative (E). In addition,heteroarylcarboxylic acid ester derivative (F) wherein X is a loweralkylene group can be produced by, during any stage in the productionsteps, conducting a step of treating with a catalyst such as 10%palladium/carbon under a hydrogen atmosphere in, for example, a solventthat does not adversely influence the reaction such as methanol,ethanol, ethyl acetate, and the like.

The esterification reaction can be performed by a known method which is,for example, (1) a method using acid halide, (2) a method using acondensation agent, and the like.

(1) The method using acid halide is performed, for example, by reactingan acid chloride obtained by reaction with thionyl chloride, oxalylchloride, and the like in a solvent that does not adversely influencethe reaction, such as dichloromethane and the like, or without solventin the presence or absence of, for example, a catalyst such asN,N-dimethylformamide and the like, with alcohol in a solvent that doesnot adversely influence the reaction such as dichloromethane,tetrahydrofuran, and the like in the presence of a base such as pyridineand triethylamine.

(2) The method using a condensation agent is performed, for example, byreacting carboxylic acid with alcohol in, for example, a solvent thatdoes not adversely influence the reaction such as tetrahydrofuran,N,N-dimethylformamide, dichloromethane, and the like in, for example,the presence or absence of a base such as pyridine, triethylamine, andthe like, by using a condensation agent such as1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSC),1,3-dicyclohexylcarbodiimide, and the like.

Heteroarylcarboxylic acid ester derivative (i) of the formula (I)wherein A is —OR5 and R5 is a hydrogen atom can be produced bysubjecting ester derivative (H) obtained by using Wittig reagent (G)(wherein E₂ is a protecting group such as a methyl group, an ethylgroup, an isopropyl group, a tert-butyl group, a benzyl group, and thelike) instead of Wittig reagent (B) to, for example, deprotection byhydrolysis with a base such as sodium hydroxide and the like, hydrolysiswith an acid such as hydrochloric acid, trifluoroacetic acid and thelike, or treating with, for example, 10% palladium/carbon and the likeunder a hydrogen atmosphere, and the like.

In addition, heteroarylcarboxylic acid ester derivative (K) of theformula (I) wherein A is a group of the formula (II) can be produced byamidating carboxylic acid, thiocarboxylic acid, or sulfonic acidderivative (i) with amine (J). The amidation reaction of carboxylic acidand thiocarboxylic acid derivative is performed using the correspondingamine instead of alcohol and in the same manner as in the aforementionedesterification reaction. The amidation reaction of the sulfonic acidderivative is performed using the corresponding amine instead of alcoholin the same manner as in (1) the method using acid halide for theaforementioned esterification reaction.

In addition, heteroarylcarboxylic acid ester derivative (K) of theformula (I) wherein A is a group of the formula (II) can also beproduced as follows.

Carboxylic acid, thiocarboxylic acid, or sulfonic acid derivative (M)can be obtained by deprotecting ester, thioester, or sulfonic acid esterderivative (L) by, for example, hydrolysis with a base such as sodiumhydroxide and the like, hydrolysis with an acid such as hydrochloricacid, trifluoroacetic acid, and the like or treatment with, for example,10% palladium/carbon and the like under a hydrogen atmosphere. Amidederivative (N) can be synthesized by amidating carboxylic acid,thiocarboxylic acid, or sulfonic acid derivative (M) with amine (J).Amide derivative (N) can be converted to carboxylic acid derivative (O)by hydrolysis in, for example, a solvent that does not adverselyinfluence the reaction, such as tetrahydrofuran, methanol, and the like,by using, for example, a base such as sodium hydroxide and the like. Theobjective heteroarylcarboxylic acid ester derivative (K) can be producedby esterifying carboxylic acid derivative (O) with amidinophenolderivative (E).

In addition, heteroarylcarboxylic acid ester derivative (S) of theformula (I) wherein Y is a thiocarbonyl group and A is a group of theformula (II) can also be produced as follows.

Thioamide derivative (Q) can be synthesized by reacting amide derivative(P) with Lawesson's reagent and the like in, for example, a solvent thatdoes not adversely influence the reaction such as toluene and the like.Thioamide derivative (Q) can be converted to carboxylic acid derivative(R) by hydrolysis in, for example, a solvent that does not adverselyinfluence the reaction, such as tetrahydrofuran, methanol, and the like,by using, for example, a base such as sodium hydroxide and the like. Theobjective heteroarylcarboxylic acid ester derivative (S) can be producedby esterifying carboxylic acid derivative (R) with amidinophenolderivative (E).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 Synthesis of 4-amidino-2-nitrophenol hydrochloride(M-8)

4-Amidinophenol hydrochloride (1.0 g, 5.8 mmol) was dissolved inconcentrated sulfuric acid (2.5 mL), and concentrated nitric acid (0.38mL) was added at −15° C. The reaction mixture was stirred for 1 hourwhile maintaining the temperature of the reaction mixture at −15° C. to−2° C., and slowly added to ice water. The mixture was neutralized byslowly adding sodium hydrogen carbonate, and the precipitated orangesolid was collected by filtration. The solid was washed with water andacetone, and suspended in methanol. 4N Hydrochloric acid/dioxane wasadded to dissolve the solid. Diisopropyl ether was added to thesolution, and the precipitated solid was collected by filtration. Thesolid was washed with diisopropyl ether and dried to give the titlecompound (0.98 g) as a pale-yellow powder.

¹H-NMR (300 MHz, DMSO-d6) δ 12.40 (1H, br), 9.36 (2H, br), 9.05 (2H,br), 8.42 (1H, d, J=2.3 Hz), 7.98 (1H, dd, J=8.9, 2, 3 Hz), 7.34 (1H, d,J=8.9 Hz).

MS (ESI) m/z 182 (M+H)+

Example 2 Synthesis of 4-amidino-2-bromophenol trifluoroacetic acid salt(M-9)

4-Amidinophenol hydrochloride (1.0 g, 5.8 mmol) was dissolved inmethanol (20 mL), the mixture was cooled to −78° C., and a solution ofbromine (0.30 mL, 5.8 mmol) in methanol (10 mL) was added slowly. Thereaction mixture was gradually warmed to room temperature and stirredovernight. The mixture was concentrated under reduced pressure and theobtained residue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound (0.24 g, 0.73 mmol, 13%).

¹H-NMR (300 MHz, DMSO-d6) δ 11.58 (1H, br), 9.12 (2H, br), 8.83 (2H,br), 8.04 (1H, d, J=2.4 Hz), 7.69 (1H, dd, J=8.7, 2.4 Hz), 7.10 (1H, d,J=8.7 Hz).

MS (ESI) m/z 215[M(⁷⁹Br)+H]⁺, 217[M(⁸¹Br)+H]⁺

Example 3 Synthesis of 4-amidino-2-chlorophenol trifluoroacetic acidsalt (M-10)

4-Amidinophenol hydrochloride (0.50 g, 2.9 mmol) was dissolved inN,N-dimethylformamide (25 mL), N-chlorosuccinimide (0.39 g, 2.9 mmol)was added, and the mixture was stirred overnight. The reaction mixturewas concentrated under reduced pressure, and the obtained residue waspurified by high performance liquid chromatography (water-acetonitrile,each containing 0.1% trifluoroacetic acid) to give the title compound(0.25 g, 0.88 mmol, 30%).

¹H-NMR (300 MHz, DMSO-d6) δ 11.50 (1H, br), 9.12 (2H, br), 8.81 (2H,br), 7.91 (1H, d, J=2.3 Hz), 7.66 (1H, dd, J=8.7, 2.3 Hz), 7.13 (1H, d,J=8.7 Hz).

MS (ESI) m/z 171 [M(³⁵Cl)+H]⁺, 173[M(³⁷Cl)+H]⁺

Example 4 Synthesis of 4-amidino-2-fluorophenol trifluoroacetic acidsalt (M-11)

To 3-fluoro-4-hydroxybenzonitrile (3.0 g) were added ethanol (3 mL) and4N hydrochloric acid-dioxane (27 mL), and the mixture was stirred atroom temperature. After 18 hours, as the mixture was concentrated anddried with a vacuum pump. Then, the mixture was dissolved in ethanol (60mL), ammonium carbonate (10.5 g) was added, and the mixture was stirredat room temperature. After 20 hours, ethanol (150 mL) was added, thesolid was filtered off, and the obtained solution was concentrated. Theresidue was purified by high performance liquid chromatography to givethe title compound (786 mg, 2.9 mmol, 13%).

¹H-NMR (300 MHz, DMSO-d6) δ 11.28 (1H, br s), 9.19 (2H, br s), 9.02 (2H,br s), 7.75 (1H, dd, J=2.4, 12.0 Hz), 7.59 (1H, m), 7.18 (1H, dd, J=8.4,8.7 Hz).

MS (ESI) m/z 155 (M+H)+

Example 5 Synthesis of 4-amidino-3-fluorophenol trifluoroacetic acidsalt (M-12)

In the same manner as in the synthesis of M-11 except that2-fluoro-4-hydroxybenzonitrile was used instead of3-fluoro-4-hydroxybenzonitrile, the title compound was obtained (yield12%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.38-8.61 (4H, br), 7.50 (1H, dd, J=9.6, 8.4Hz), 6.78-6.73 (2H, m).

MS (ESI) m/z 155 (M+H)+

Example 6 Synthesis of 2-(diethylphosphono)propanoic acid tert-butylester (M-13)

2-Bromo-propanoic acid tert-butyl ester (17.4 g, 83 mmol) and triethylphosphite (14.5 g, 87 mmol) were mixed, and the mixture was stirred at110° C. overnight. The reaction mixture was dried under reduced pressureto give the title compound (23.9 g).

¹H-NMR (300 MHz, CDCl₃) δ 4.20-4.08 (4H, m), 2.92 (1H, dq, J=30.6, 7.2Hz), 1.48 (9H, s), 1.45 (3H, d, J=7.2 Hz), 1.40-1.30 (6H, m).

Example 7 Synthesis of 2-(diethylphosphono)butanoic acid tert-butylester (M-14)

Diethylphosphonoacetic acid tert-butyl ester (1.0 g, 4.0 mmol) wasdissolved in N,N-dimethylformamide (1.4 mL), and 60% sodium hydride(0.17 g, 4.4 mmol) was added at 0° C. After stirring at room temperaturefor 30 minutes, the reaction mixture was cooled again to 0° C., ethyliodide (0.33 mL, 4.1 mmol) was added, and the mixture was stirred atroom temperature overnight. The reaction mixture was diluted with ethylacetate, washed successively with 0.5N hydrochloric acid, water andsaturated brine, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (ethylacetate/hexane=57/43) to give the title compound (0.92 g, 3.3 mmol,83%).

¹H-NMR (300 MHz, CDCl₃) δ 4.20-4.09 (4H, m), 2.76 (1H, ddd, J=22.1,10.4, 4.3 Hz), 2.00-1.83 (2H, m), 1.48 (9H, s), 1.35 (3H, t, J=7.2 Hz),1.34 (3H, t, J=7.1 Hz), 0.99 (3H, td, J=7.5, 1.1 Hz).

Example 8 Synthesis of 2-(diethylphosphono)pentanoic acid tert-butylester (M-15)

In the same manner as in the synthesis of M-14 except that propylbromide was used instead of ethyl iodide, the title compound wasobtained (yield 77%).

¹H-NMR (300 MHz, CDCl₃) δ 4.20-4.09 (4H, m), 2.85 (1H, ddd, J=22.3,11.2, 3.8 Hz), 2.05-1.73 (4H, m), 1.47 (9H, s), 1.45-1.29 (6H, m), 0.93(3H, t, J=7.2 Hz).

Example 9 Synthesis of 1-(diethylphosphono)ethanesulfonic acid isopropylester (M-16) Step 1. Synthesis of Ethanesulfonic Acid Isopropyl Ester

To a solution of 2-propanol (2.4 mL, 32 mmol) in dichloromethane (50mL), were added triethylamine (3.5 ml, 25 mmol) and ethanesulfonylchloride (2.0 mL, 21 mmol), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was washed successivelywith 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonateand saturated brine, and dried over sodium sulfate. The drying agent wasfiltered off, and the filtrate was concentrated under reduced pressureto give the title compound (2.4 g, 16 mmol, 75%).

¹H-NMR (300 MHz, CDCl₃) δ 4.81 (1H, sep, J=6.4 Hz), 3.25 (2H, q, J=7.3Hz), 1.30 (6H, d, J=6.4 Hz), 1.21 (3H, t, J=7.3 Hz).

Step 2. Synthesis of 1-(diethylphosphono)ethanesulfonic acid isopropylester (M-16)

A solution of ethanesulfonic acid isopropyl ester (1.0 g, 6.6 mmol) intetrahydrofuran (15 mL) was cooled to −78° C., and n-butyllithium (1.57M, 4.6 mL, 7.2 mmol) was added. After stirring at −78° C. for 20minutes, diethyl chlorophosphate (0.52 mL, 3.6 mmol) was added to thereaction mixture, and the mixture was further stirred for 30 minutes. 1NHydrochloric acid was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over sodium sulfate. The solvent wasevaporated under reduced pressure and the obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=40/60) to givethe title compound (0.61 g, 2.1 mmol, 58%).

¹H-NMR (300 MHz, CDCl₃) δ 5.08 (1H, sep, J=6.3 Hz), 4.29-4.18 (4H, m),3.57 (1H, dq, J=19.2, 7.3 Hz), 1.69 (3H, dd, J=15.6, 7.3 Hz), 1.45 (6H,d, J=6.3 Hz), 1.37 (6H, t, J=6.9 Hz).

Example 10 Synthesis of5-[(1E)-2-(tert-butoxycarbonyl)-prop-1-en-1-yl]furan-2-carboxylic acid(M−1) Step 1. Synthesis of5-[(1E)-2-(tert-butoxycarbonyl)-prop-1-en-1-yl]furan-2-carboxylic acidmethyl ester

5-Formyl-2-furancarboxylic acid (5 g, 35.7 mmol) was dissolved inacetone (100 mL), and trimethylsilyl-diazomethane/2M hexane solution(23.2 mL, 46.4 mmol) was slowly added dropwise at room temperature.After stirring at room temperature for 10 minutes, the solvent wasevaporated under reduced pressure to give 5-formyl-2-furancarboxylicacid methyl ester as a crude product.

A tetrahydrofuran solution (30 mL) of M-13 (14.3 g, 53.6 mmol) was addeddropwise to a stirring suspension of 60% sodium hydride (1.86 g, 46.4mmol) in tetrahydrofuran (120 mL) at 0° C. The mixture was stirred atroom temperature for 30 minutes, and a tetrahydrofuran solution (30 mL)of the crude product obtained earlier was added dropwise at 0° C. Afterstirring at room temperature overnight, the mixture was worked upaccording to a conventional method, and the object product was extractedby column chromatography (5-10% ethyl acetate/hexane mixed solvent) togive the title compound (5.55 g, 20.8 mmol, 2 steps 58%).

¹H-NMR (300 MHz, CDCl₃) δ 7.39 (1H, d, J=0.9 Hz), 7.22 (1H, a, J=3.6Hz), 6.64 (1H, d, J=3.6 Hz), 3.92 (3H, s), 2.21 (3H, d, J=0.9 Hz), 1.53(9H, s).

MS (ESI) m/z 267 (M+H)+

Step 2. Synthesis of5-[(1E)-2-(tert-butoxycarbonyl)-prop-1-en-1-yl]furan-2-carboxylic acid(M−1)

5-[(1E)-2-(tert-butoxycarbonyl)-prop-1-en-1-yl]furan-2-carboxylic acidmethyl ester (1.11 g, 4.17 mmol) obtained in step 1 was dissolved inmethanol (7.65 mL), 1N aqueous lithium hydroxide solution (6.25 mL, 6.25mmol) was added, and the mixture was stirred at room temperature for 100minutes. 1N aqueous hydrochloric acid solution (6.25 mL) was added, themixture was stirred for 10 minutes, and the solvent was evaporated underreduced pressure. To the residue were added ethyl acetate and 0.5Naqueous hydrochloric acid solution, the organic layer was extracted, andthe aqueous layer was extracted three times with ethyl acetate. Theorganic layers were collected, washed with saturated brine and dried bydehydration with sodium sulfate. The solvent of the filtrate afterfiltration was evaporated under reduced pressure to give the titlecompound.

¹H-NMR (300 MHz, DMSO-d6) δ 7.33-7.25 (2H, m), 6.98 (1H, d, J=3.6 Hz),2.15 (3H, s), 1.48 (9H, s).

MS (ESI) m/z 253 (M+H)+

Example 11 Synthesis of5-(2-tert-butoxycarbonylpropyl)furan-2-carboxylic acid (M-2) Step 1.Synthesis of 5-(2-tert-butoxycarbonylpropyl)-furan-2-carboxylic acidmethyl ester

(2E)-(5-Methoxycarbonylfuran-2-yl)-2-methylpropenoic acid tert-butylester (2.96 g, 11.1 mmol) was dissolved in methanol (100 mL), 10%palladium/carbon (0.3 g) was added, and the mixture was stirred at roomtemperature for 2 hours under a hydrogen atmosphere. After completion ofthe reaction, palladium/carbon was removed by celite filtration, and thesolvent was evaporated under reduced pressure to give the title compound(2.72 g).

¹H-NMR (300 MHz, DMSO-d6) δ 7.20 (1H, d, J=3.3 Hz), 6.35 (1H, d, J=3.3Hz), 3.76 (3H, s), 2.90-2.60 (3H, m), 1.34 (9H, s), 1.07 (3H, d, J=6.9Hz).

Step 2. Synthesis of 5-(2-tert-butoxycarbonylpropyl)-furan-2-carboxylicacid (M-2)

5-(2-tert-Butoxycarbonylpropyl)furan-2-carboxylic acid methyl ester (1.0g, 3.76 mmol) obtained in step 1 was dissolved in tetrahydrofuran (4.5mL) and methanol (3 mL), 1N aqueous sodium hydroxide solution (4.5 mL)was added, and the mixture was stirred overnight. The mixture wasneutralized with 1N hydrochloric acid, extracted with ethyl acetate, andwashed successively with water and saturated brine. After drying overanhydrous magnesium sulfate, the drying agent was filtered off, and thesolvent was evaporated to give the title compound (0.98 g).

¹H-NMR (300 MHz, DMSO-d6) δ 7.11 (1H, s), 6.32 (1H, s), 2.95-2.65 (3H,m), 2.50 (3H, s), 1.35 (9H, s).

MS (ESI) m/z 253 (M+H)+

Example 12 Synthesis of5-[(1E)-2-(tert-butoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylicacid (M-3) Step 1. Synthesis of5-[(1E)-2-(tert-butoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylicacid methyl ester

M-13 (2.08 g, 7.8 mmol) was dissolved in tetrahydrofuran (30 mL), 60%sodium hydride (0.37 g, 9.25 mmol) was added at 0° C., and the mixturewas stirred for 30 minutes. To the reaction mixture was added a solutionof 5-formyl-2-thiophenecarboxylic acid methyl ester (1.02 g, 6.0 mmol)in tetrahydrofuran (5 mL), and the mixture was stirred at roomtemperature overnight. The solvent was evaporated, and the residue waspartitioned between ethyl acetate and 1N hydrochloric acid, and washedsuccessively with water and saturated brine. After drying over anhydrousmagnesium sulfate, the residue was purified by silica gel columnchromatography to give the title compound (1.18 g).

¹H-NMR (300 MHz, CDCl₃) δ 7.75 (1H, d, J=4.2 Hz), 7.69 (1H, s), 7.19(1H, d, J=4.2 Hz), 3.90 (3H, s), 2.19 (3H, s), 1.54 (9H, s).

Step 2. Synthesis of5-[(1E)-2-(tert-butoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylicacid (M-3)

5-[(1E)-2-(tert-Butoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylicacid methyl ester (1.18 g, 4.19 mmol) obtained in step 1 was dissolvedin tetrahydrofuran (5 mL), 1N aqueous lithium hydroxide solution (4.6mL) was added, and the mixture was stirred overnight. The mixture wasneutralized with 1N hydrochloric acid, and extracted with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated to give the title compound (1.06 g).

¹H-NMR (300 MHz, CDCl₃) δ 7.70 (1H, d, J=3.9 Hz), 7.66 (1H, s), 7.63(1H, d, J=3.9 Hz), 7.16 (1H, d, J=3.9 Hz), 2.16 (3H, s), 1.51 (9H, s).

MS (ESI) m/z 269 (M+H)+

Example 13 Synthesis of5-(2-tert-butoxycarbonylpropyl)-thiophene-2-carboxylic acid (M-4)

Using5-[(1E)-2-(tert-butoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylicacid methyl ester obtained in Example 12, step 1 and in the same manneras in Example 11, the title compound was obtained.

¹H-NMR (300 MHz, CDCl₃) δ 7.72 (1H, d, J=3.6 Hz), 6.85 (1H, d, J=3.6Hz), 3.24-2.65 (3H, m), 1.42 (9H, s), 1.19 (3H, d, J=6.9 Hz).

MS (ESI) m/z 271 (M+H)+

Example 14 Synthesis of 2-[{3-triisopropylsilyloxypropyl}-amino]aceticacid tert-butyl ester (M-5)

To a solution of 3-amino-1-propanol (2.0 mL, 26 mmol) in dichloromethane(20 mL) was added triisopropylsilyl trifluoromethanesulfonate (7.2 mL,27 mmol), and the mixture was stirred at room temperature for 1 hour.Triethylamine (3.7 mL, 26 mmol) and bromoacetic acid tert-butyl ester(3.1 mL, 21 mmol) were added to the reaction mixture, and the mixturewas further stirred at room temperature for 1 hour. The reaction mixturewas diluted with dichloromethane and washed with saturated aqueoussodium hydrogen carbonate. The organic layer was dried over sodiumsulfate and concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography(dichloromethane/methanol=97/3) to give the title compound (1.85 g, 5.4mmol, 25%).

¹H-NMR (300 MHz, CDCl₃) δ 3.96 (2H, t, J=5.4 Hz), 3.80 (2H, s), 3.34(2H, t, J=5.9 Hz), 2.03 (2H, m), 1.50 (9H, s), 1.17-1.07 (21H, m).

Example 15 Synthesis of N-(3-triisopropylsilyloxypropyl)-taurineisopropyl ester (M-7) Step 1. Synthesis of vinylsulfonic acid isopropylester

2-Chloroethylsulfonyl chloride (2 g, 12.3 mmol), isopropanol (1 mL), andpyridine (2.7 mL) were dissolved in dichloromethane (20 mL), and themixture was stirred at room temperature for 3 hours. The reactionmixture was washed successively with 1N hydrochloric acid and water, andthe organic layer was dried over anhydrous magnesium sulfate. The dryingagent was filtered, and the solvent was evaporated to give the titlecompound (1.06 g).

¹H-NMR (300 MHz, CDCl₃) δ 6.56 (1H, dd, J=9.9, 16.8 Hz), 6.39 (1H, d,J=16.8 Hz), 6.07 (1H, d, J=9.9 Hz), 4.81 (1H, sep, J=6.3 Hz), 1.40 (6H,d, J=6.3 Hz).

Step 2. Synthesis of N-(3-triisopropylsilyloxypropyl)-taurine isopropylester (M-7)

Vinylsulfonic acid isopropyl ester (0.3 g, 2.00 mmol) obtained in step 1and 3-triisopropylsilyloxypropylamine (0.9 g, 3.89 mmol) were dissolvedin methanol (10 mL), and the mixture was stirred at room temperatureovernight. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound (0.65 g).

¹H-NMR (300 MHz, CDCl₃) δ 4.97 (1H, sep, J=6.0 Hz), 3.78 (2H, t, J=6.9Hz), 3.29 (2H, t, J=6.9 Hz), 3.13 (2H, t, J=6.9 Hz), 2.78 (2H, t, J=6.9Hz), 1.74 (2H, m), 1.42 (6H, d, J=6.0 Hz), 1.05 (21H, m).

Example 16 Synthesis of(2E)-3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-methylpropenoic acidtrifluoroacetic acid salt (A-3)

M-1, 4-hydroxybenzamidine hydrochloride (712 mg, 4.17 mmol) and WSChydrochloride (869 mg, 4.53 mmol) were dissolved in pyridine (10 mL),and the mixture was stirred at room temperature overnight. The solventwas evaporated under reduced pressure, trifluoroacetic acid (10 mL) wasadded, and the mixture was stirred at room temperature for 15 minutes.The solvent was evaporated under reduced pressure, and the resultantsolid was washed with diethyl ether, collected by filtration withKiriyama funnel, and dried in a desiccator to give the title compound(1.46 g, 3.41 mmol, 3 steps 82%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 8.95 (2H, br s), 7.91 (2H,d, J=8.7 Hz), 7.72 (1H, d, J=3.9 Hz), 7.59 (2H, d, J=8.7 Hz), 7.43 (1H,s), 7.14 (1H, d, J=3.9 Hz), 2.73 (1H, s), 2.24 (3H, s).

MS (ESI) m/z 315 (M+H)+

Example 17 Synthesis of3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2-methylpropionic acidtrifluoroacetic acid salt (A-6)

10% Palladium/carbon (49.5 mg) and A-3 (495 mg, 1.16 mmol) weresuspended in methanol (3.0 mL), and the suspension was stirred at roomtemperature overnight under a hydrogen atmosphere (1 atm). Aftercompletion of the reaction, palladium/carbon was removed by celitefiltration. The solvent was evaporated under reduced pressure, and theobject product was extracted by high performance liquid chromatography(10-40% water (containing 0.1% trifluoroacetic acid)/acetonitrile(containing 0.1% trifluoroacetic acid) mixed solvent) to give the titlecompound (246 mg, 0.57 mmol, 49.3%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.10 (2H, br s), 7.90 (2H,d, J=6.9 Hz), 7.61-7.52 (3H, m), 6.52 (1H, d, J=3.6 Hz), 3.13-2.98 (1H,m), 2.91-2.70 (2H, m), 1.14 (3H, d, J=6.9 Hz).

MS (ESI) m/z 317 (M+H)+

Example 18 Synthesis ofN-{(2E)-3-[5-(4-amidino-2-phenoxycarbonyl)furan-2-yl]-2-methylpropenoyl}-N-(3-hydroxypropyl)-β-alaninetrifluoroacetic acid salt (A-12) Step 1. Synthesis of3-triisopropylsilyloxypropylamine

3-Hydroxylpropylamine (100 μL, 1.31 mmol) was dissolved indichloromethane (4.4 mL), and triisopropylsilyl triflate (371 μL, 1.38mmol) was added dropwise at room temperature. After stirring at roomtemperature for 15 minutes, the mixture was worked up according to aconventional method to give the title compound as a crude product.

Step 2. Synthesis of N-(3-triisopropylsilyloxypropyl)-β-alaninetert-butyl ester (M-6)

The crude product obtained in step 1 was dissolved in toluene (3.0 mL),acrylic acid tert-butyl ester (173 μL, 1.19 mmol) was added, and themixture was stirred under reflux for 6 hours. The solvent was evaporatedunder reduced pressure, and crudely purified by silica gel columnchromatography (0-4% methanol/dichloromethane mixed solvent) to give thetitle compound as a crude product.

Step 3. Synthesis ofN-{(2E)-3-[5-(4-amidino-2-phenoxycarbonyl)furan-2-yl]-2-methylpropenoyl}-N-(3-hydroxypropyl)-β-alaninetrifluoroacetic acid salt (A-12)

A-3 (87 mg, 0.20 mmol) was dissolved in thionyl chloride (500 μL), andthe mixture was stirred at 70° C. for 10 minutes. Thionyl chloride wasevaporated under reduced pressure to give acid chloride. The obtainedacid chloride was dissolved in dichloromethane (500 μL), the amineobtained in step 2 and pyridine (250 μL) were added thereto, and themixture was stirred at room temperature for 30 minutes. Afterevaporation of the solvent, trifluoroacetic acid (500 μL: containing 5%water) was added, and the mixture was stirred at room temperatureovernight. Trifluoroacetic acid was evaporated under reduced pressure,saturated aqueous sodium hydrogen carbonate solution (1 mL) was added,and the mixture was stirred for 1 hour. The object product was extractedby high performance liquid chromatography (5-35% water (containing 0.1%trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroaceticacid) mixed solution) to give the title compound (4.0 mg, 0.007 mmol,3.5%).

MS (ESI) m/z 444 (M+H)+

Example 19 Synthesis ofN-{(2E)-3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2-methylpropenyl}-L-glutamicacid trifluoroacetic acid salt (A-13)

A-3 (49 mg, 0.11 mmol) was dissolved in thionyl chloride (0.5 mL), andthe mixture was heated at 70° C. for 5 minutes. Thionyl chloride wasevaporated under reduced pressure, and the obtained residue wasdissolved in dichloromethane (0.35 mL). Glutamic acid di-tert-butylester hydrochloride (50.8 mg, 0.17 mmol) and pyridine (0.15 mL) wereadded, and the mixture was stirred at room temperature for 40 minutes.The solvent was, evaporated under reduced pressure, trifluoroacetic acid(0.5 mL: containing 5% water) was added, and the mixture was stirred atroom temperature for 2 hours. The solvent was evaporated again, water(0.5 mL) was added, and the mixture was stirred at room temperatureovernight. The solvent was evaporated under reduced pressure, and theobject product was extracted by high performance liquid chromatography(5-35% water (containing 0.1% trifluoroacetic acid)/acetonitrile(containing 0.1% trifluoroacetic acid) mixed solution) to give the titlecompound (32 mg, 0.06 mmol, 50%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.02 (2H, br s), 8.35 (1H,d, J=7.5 Hz), 7.91 (2H, d, J=6.7 Hz), 7.72 (1H, d, J=3.3 Hz), 7.59 (2H,d, J=7.5 Hz), 7.18 (1H, s), 7.04 (1H, d, J=3.3 Hz), 4.35-4.22 (2H, m),2.42-2.30 (2H, m), 2.22 (3H, s), 2.15-1.81 (2H, m).

MS (ESI) m/z 444 (M+H)+

Example 20 Synthesis of3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2-ethylpropionic acidtrifluoroacetic acid salt (A-29) Step 1. Synthesis of[5-(benzyloxycarbonyl)furan-2-yl]-2-ethylpropenoic acid tert-butyl ester

5-Formyl-2-furancarboxylic acid benzyl ester (200 mg, 0.87 mmol) andM-14 (364.4 mg, 1.30 mmol) were dissolved in tetrahydrofuran (3.0 mL),and 60% sodium hydride (45.3 mg, 1.13 mmol) was added at 0° C. Afterremoving from the ice bath, the mixture was stirred at room temperaturefor 30 minutes. The mixture was worked up according to a conventionalmethod to give the title compound as a crude product.

Step 2. Synthesis of 3-(5-hydroxycarbonylfuran-2-yl)-2-ethylpropionicacid tert-butyl ester

The crude product obtained in step 1 and 10% palladium/carbon (30 mg)were suspended in ethanol (3.0 mL), and the suspension was stirredovernight at ambient temperature and normal pressure under a hydrogenatmosphere. Palladium/carbon was removed by celite filtration, and thesolvent was evaporated under reduced pressure to give the title compoundas a crude product.

Step 3. Synthesis of3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-ethylpropionic acidtrifluoroacetic acid salt (A-29)

The crude product obtained in step 2 and 4-hydroxybenzamidinehydrochloride (180 mg, 1.04 mmol) were dissolved in pyridine (3.0 mL),and WSC hydrochloride (217 mg, 1.13 mmol) was added with stirring atroom temperature. After stirring at room temperature for 100 minutes,the solvent was evaporated under reduced pressure. Trifluoroacetic acid(3.0 mL) was added to the obtained residue, and the mixture was stirredat room temperature for 15 minutes. The solvent was evaporated, and theobject product was extracted by column chromatography (5-35% water(containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1%trifluoroacetic acid) mixed solvent) to give the title compound (225 mg,0.57 mmol, 3 steps 66%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.13 (2H, br s), 7.90 (2H,d, J=8.7 Hz), 7.63-7.49 (3H, m), 6.51 (1H, d, J=3.6 Hz), 3.10-2.82 (2H,m), 2.69-2.55 (1H, m), 1.64-1.49 (2H, m), 0.90 (3H, t, J=7.5 Hz).

MS (ESI) m/z 331 (M+H)+

Example 21 Synthesis of N-[5-(4-amidinophenoxycarbonyl)furan-2-ylaceticacid trifluoroacetic acid salt (A-32) Step 1. Synthesis of5-ethoxycarbonylfuran-2-ylacetic acid

5-Chloromethyl-2-furancarboxylic acid ethyl ester (1.0 g, 5.3 mmol),potassium iodide (0.044 g, 0.27 mmol), andchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.26 g, 0.53 mmol) weredissolved in formic acid (25 mL), and the mixture was stirred at 75° C.for 6 hours under a carbon monoxide atmosphere. The solvent wasevaporated, and the residue was partitioned between ethyl acetate andaqueous sodium hydrogen carbonate solution. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thedrying agent was filtered off, the solvent was evaporated, and theresidue was purified by silica gel column chromatography to give thetitle compound (0.61 g).

¹H-NMR (300 MHz, CDCl₃) δ 7.13 (1H, d, J=3.6 Hz), 6.42 (1H, d, J=3.6Hz), 4.35 (2H, q, J=7.5 Hz), 3.83 (2H, s), 1.37 (3H, t, J=7.5 Hz).

MS (ESI) m/z 199 (M+H)+

Step 2. Synthesis of 5-ethoxycarbonylfuran-2-ylacetic acid tert-butylester

5-Ethoxycarbonylfuran-2-ylacetic acid (0.61 g, 3.08 mmol) obtained instep 1 was dissolved in thionyl chloride (10 mL), and the mixture wasstirred at 70° C. for 1 hour. The solvent was evaporated under reducedpressure, tert-butanol (5 mL) and triethylamine (2 mL) were added, andthe mixture was stirred for 30 minutes. The solvent was evaporated, andthe residue was purified by silica gel column chromatography to give thetitle compound (0.37 g).

¹H-NMR (300 MHz, CDCl₃) δ 7.13 (1H, d, J=3.3 Hz), 6.36 (1H, d, J=3.3Hz), 4.35 (2H, q, J=6.9 Hz), 3.68 (2H, s), 1.25 (9H, s), 1.25 (3H, t,J=6.9 Hz).

Step 3. Synthesis of 5-tert-butoxycarbonylmethyl-2-furancarboxylic acid

5-Ethoxycarbonylfuran-2-ylacetic acid tert-butyl ester (0.37 g, 1.46mmol) obtained in step 2 was dissolved in tetrahydrofuran (2 mL),dissolved in 1N aqueous sodium hydroxide solution (1.5 mL), and themixture was stirred overnight. 1N Hydrochloric acid (1.5 mL) was addedto the reaction mixture, and the mixture was neutralized, purified byhigh performance liquid chromatography and freeze-dried to give thetitle compound (80 mg).

¹H-NMR (300 MHz, CDCl₃) δ 7.26 (1H, d, J=3.6 Hz), 6.42 (1H, d, J=3.6Hz), 3.70 (2H, s), 1.47 (9H, s).

Step 4. Synthesis of 5-(4-amidinophenoxycarbonyl)furan-2-ylacetic acidtrifluoroacetic acid salt (A-32)

5-tert-Butoxycarbonylmethyl-2-furancarboxylic acid (80 mg, 0.24 mmol)obtained in step 3 and 4-hydroxybenzamidine hydrochloride (80 mg, 0.46mmol) were dissolved in pyridine (5 mL), WSC hydrochloride (0.10 g, 0.52mmol) was added, and the mixture was stirred overnight. Afterevaporation of the solvent, trifluoroacetic acid (5 mL) was added, andthe mixture was stirred for 30 minutes. The mixture was purified by highperformance liquid chromatography and freeze-dried to give the titlecompound.

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.01 (2H, s), 7.89 (2H, J=8.7Hz), 6.64 (1H, d, J=3.6 Hz), 7.57 (3H, m), 3.89 (2H, s).

MS (ESI) m/z 289 (M+H)+

Example 22 Synthesis ofN-(3-[5-(4-amidino-2-fluorophenoxycarbonyl)furan-2-yl]-2-methylpropanoyl)-N-(D)-asparticacid trifluoroacetic acid salt (A-35)

A-33 (68 mg, 0.15 mmol) and (D)-aspartic acid dibenzyl ester4-toluenesulfonate (96 mg, 0.20 mmol) were dissolved in pyridine (0.5mL), WSC hydrochloride (44 mg, 0.23 mmol) was added, and the mixture wasstirred at room temperature overnight. After evaporation of the solvent,ethanol (2 mL) and 10% palladium/carbon (10 mg) were added, and themixture was stirred at room temperature overnight under a hydrogenatmosphere. The reaction mixture was filtered through celite, and thefiltrate was concentrated under reduced pressure to give a residue. Theobtained residue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound (12.7 mg).

¹H-NMR (DMSO-d6) δ 9.42 (br s, 2H), 9.19 (br s, 2H), 8.42-8.31 (m, 1H),7.93 (d, J=11.4 Hz, 1H), 7.81-7.69 (m, 2H), 7.61-7.56 (m, 1H), 6.56-6.45(m, 1H), 4.61-4.42 (m, 1H), 3.11-2.88 (m, 2H), 2.87-2.47 (m, 3H), 1.06(t, J=6.6 Hz, 1H).

MS (ESI) m/z 450 (M+H)+

Example 23 Synthesis of1-[5-(4-amidinophenoxycarbonyl)furan-2-yl]propane-2-sulfonic acidtrifluoroacetic acid salt (A-36) Step 1. Synthesis of isopropyl1-[5-(benzyloxycarbonyl)-furan-2-yl]propane-2-sulfonate

Using M-16 and 4-hydroxybenzamidine hydrochloride and by an operation inthe same manner as in Example 20, the title compound was obtained.

¹H-NMR (300 MHz, CDCl₃) δ 7.46-7.33 (6H, m), 7.25 (1H, d, J=3.7 Hz),6.71 (1H, d, J=3.7 Hz), 5.36 (2H, s), 4.77 (1H, sep, J=6.2 Hz), 2.45(1H, d, J=1.2 Hz), 1.39 (3H, d, J=6.2 Hz).

Step 2. Synthesis of1-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]propane-2-sulfonic acidtrifluoroacetic acid salt (A-36)

Isopropyl 1-[5-(benzyloxycarbonyl)furan-2-yl]propane-2-sulfonateobtained in step 1 was stirred in 4N hydrochloric acid overnight, andthe mixture was purified by high performance liquid chromatography andfreeze-dried to give the title compound.

¹H-NMR (300 MHz, DMSO-d6) δ 9.32 (2H, br), 8.90 (2H, br), 7.87 (2H, d,J=8.7 Hz), 7.55 (2H, d, J=8.7 Hz), 7.51 (1H, d, J=3.6 Hz), 6.54 (1H, d,J=3.6 Hz), 2.73-2.57 (3H, m), 1.05 (3H, d, J=6.9 Hz).

MS (ESI) m/z 353 (M+H)+

Example 24 Synthesis ofN-[5-(4-amidinophenoxycarbonyl)furan-2-ylacetyl]-(L)-aspartic acidtrifluoroacetic acid salt (A-39)

5-Carboxymethyl-2-furancarboxylic acid (117 mg, 0.69 mmol) obtained as abyproduct in Example 21, step 3 and L-aspartic acid di-tert-butyl esterhydrochloride (193 mg, 0.68 mmol) were dissolved in dichloromethane (5mL), WSC hydrochloride (158 mg, 0.82 mmol) and triethylamine (0.5 mL)were added, and the mixture was stirred overnight. After evaporation ofthe solvent, the residue was purified by high performance liquidchromatography and freeze-dried. The obtained solid (31 mg) and4-hydroxybenzamidine hydrochloride (15 mg, 0.087 mmol) were dissolved inpyridine (5 mL), WSC hydrochloride (30 mg, 0.16 mmol) was added, and themixture was stirred overnight. After evaporation of the solvent,trifluoroacetic acid (5 mL) was added, and the mixture was stirred for30 min. The mixture was purified by high performance liquidchromatography and freeze-dried to give the title compound (23 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.09 (2H, s), 8.55 (1H, d,J=7.8 Hz), 7.89 (2H, d, J=8.7 Hz), 7.56 (3H, m), 6.58 (1H, d, J=3.6 Hz),4.53 (1H, m), 2.89 (2H, s), 2.64 (2H, m).

MS (ESI) m/z 404 (M+H)+

Example 25 Synthesis of(2E)-3-[5-(4-amidinophenoxycarbonyl)-thiophen-2-yl]-2-methylpropenoicacid trifluoroacetic acid salt (B−1) Step 1. Synthesis of3-[5-(4-amidinophenoxycarbonyl)-thiophen-2-yl]-2-methylpropenoic acidtert-butyl ester

5-(2-(tert-Butoxycarbonyl)-1-propenyl)-2-thiophenecarboxylic acid (0.51g, 1.89 mmol) and 4-hydroxybenzamidine hydrochloride (0.33 g, 1.89 mmol)were dissolved in pyridine (10 mL), WSC hydrochloride (0.54 g, 2.8 mmol)was added, and the mixture was stirred overnight. The mixture waspurified by high performance liquid chromatography and freeze-dried togive the title compound (0.63 g).

¹H-NMR (300 MHz, DMSO-d6) δ 9.33 (2H, s), 8.98 (2H, s), 8.07 (1H, d,J=3.9 Hz), 7.89 (2H, d, J=8.7 Hz), 7.78 (1H, s), 7.63 (1H, d, J=3.9 Hz),7.58 (1H, d, J=8.7 Hz), 2.15 (3H, s), 1.49 (9H, s).

Step 2. Synthesis of(2E)-3-[5-(4-amidinophenoxycarbonyl)thiophen-2-yl]-2-methylpropenoicacid trifluoroacetic acid salt (B−1)

To 3-[5-(4-amidinophenoxycarbonyl)thiophen-2-yl]-2-methylpropenoic acidtert-butyl ester (0.63 g) was added trifluoroacetic acid (5 mL), and themixture was stirred for 30 minutes. The solvent was evaporated to givethe title compound (0.62 g).

¹H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, s), 9.00 (2H, s), 8.09 (1H, d,J=3.9 Hz), 7.88 (3H, m), 7.60 (3H, m), 2.18 (3H, s).

MS (ESI) m/z 331 (M+H)+

Example 26 Synthesis of3-[5-(4-amidinophenoxycarbonyl)-thiophen-2-yl]-2-methylpropanoic acidtrifluoroacetic acid salt (B-6)

B-1 (50 mg, 0.11 mmol) was dissolved in a mixed solution ofethanol/water (1/1, 5 mL), a catalytic amount of 10% palladium/carbonwas added, and the mixture was stirred at room temperature for 5 hoursunder a hydrogen atmosphere. The reaction mixture was filtered, and thesolvent was evaporated to give the title compound.

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.01 (2H, s), 7.91 (2H, m),7.56 (1H, d, J=9.0 Hz), 7.10 (1H, d, J=3.6 Hz), 3.37 (1H, m), 3.01 (1H,m), 2.73 (1H, m), 1.13 (3H, d, J=4.2 Hz).

MS (ESI) m/z 333 (M+H)+

Example 27 Synthesis ofN-{(2E)-3-[5-(4-amidinophenoxycarbonyl)thiophen-2-yl]-2-methylpropenoyl}-N-hydroxypropyltaurinetrifluoroacetic acid salt (B-7)

B-1 (30 mg, 0.068 mmol) was suspended in thionyl chloride (4 mL), andthe suspension was stirred at 70° C. for 30 minutes. After evaporationof the solvent, dichloromethane (2 mL), M-7 (25 mg, 0.072 mmol) andpyridine (50 μL) were added, and the mixture was stirred for 30 minutes.After evaporation of the solvent, trifluoroacetic acid (3 mL) was added,and the mixture was stirred for 30 minutes. After evaporation of thesolvent, 4M hydrochloric acid (2 mL) and acetonitrile (0.5 mL) wereadded, and the mixture was stirred at room temperature for 2 days. Themixture was purified by high performance liquid chromatography andfreeze-dried to give the title compound (4.9 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, s), 8.91 (2H, s), 8.03 (1H, d,J=4.2 Hz), 7.90 (2H, d, J=8.7 Hz), 7.60 (2H, d, J=8.7 Hz), 7.40 (1H, d,J=4.2 Hz), 6.84 (1H, s), 4.48 (1H, br s), 3.55 (2H, m), 3.20-3.45 (4H,m), 2.70 (2H, m), 2.15 (3H, s), 1.67 (2H, m).

MS (ESI) m/z 496 (M+H)+

Example 28 Synthesis ofN-{3-[5-(4-amidino-2-nitrophenoxycarbonyl)thiophen-2-yl]-2-methylpropanoyl}-N-(3-hydroxypropyl)glycinehydrochloride (B-11) Step 1. Synthesis ofN-{(1E)-3-[5-(methoxycarbonyl)-thiophen-2-yl]-2-methylpropenoyl}-N-[3-(triisopropylsilyloxy)-propyl]glycinetert-butyl ester

To5-[(1E)-2-(tert-butoxycarbonyl)-2-methyl-prop-1-en-1-yl]thiophene-2-carboxylicacid methyl ester (600 mg, 2.13 mmol) obtained in Example 12, step 1 wasadded trifluoroacetic acid (5 mL), and the mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was concentrated underreduced pressure. The obtained residue was dissolved in dichloromethane(15 mL), oxalyl chloride (0.37 mL, 4.26 mmol) and N,N-dimethylformamide(50 μL) were added, and the mixture was stirred at room temperature for15 minutes. The reaction mixture was concentrated under reducedpressure, the obtained residue was dissolved in dichloromethane (10 mL),and M-5 (0.81 g, 2.34 mmol) obtained in step 1 and pyridine (5 mL) wereadded. After stirring at room temperature for 15 minutes, the reactionmixture was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (hexane/ethylacetate=80/20) to give the title compound (477 mg, 0.86 mmol, 40%).

MS (ESI) m/z 554 (M+H)+

Step 2. Synthesis ofN-{3-[5-(4-amidino-2-nitrophenoxycarbonyl)thiophen-2-yl]-2-methylpropanoyl}-N-(3-hydroxypropyl)glycinehydrochloride (B-11)

The compound (477 mg, 0.86 mmol) obtained in step 1 was dissolved intetrahydrofuran (15 mL) and methanol (3 mL), and water (1 mL), and 1Naqueous sodium hydroxide solution (1.0 mL, 1.0 mmol) were added thereto.After stirring at room temperature for 22 hours, 1N aqueous sodiumhydroxide solution (0.43 mL, 0.43 mmol) was added to the reactionmixture, and the mixture was further stirred for 4 hours. 1N Aqueoussodium hydroxide solution (1.2 mL, 1.2 mmol) was added to the reactionmixture, and the mixture was stirred for 3 hours and acidified with 1Nhydrochloric acid. To the reaction mixture was added saturated brine,and the mixture was extracted three times with dichloromethane. Theextract was dried over sodium sulfate, and the solvent was evaporatedunder reduced pressure to give a residue (430 mg).

The obtained residue (400 mg) was dissolved in ethanol (12 mL) andchloroform (50 μL), 10% palladium/carbon (40 mg) was added, and themixture was stirred at room temperature overnight under a hydrogenatmosphere. The reaction mixture was filtered through celite, and thefiltrate was concentrated under reduced pressure to give a residue (335mg).

To the obtained residue (335 mg) were added M-8 (209 mg, 0.96 mmol), WSChydrochloride (169 mg, 0.88 mmol), and pyridine (33 mL), and the mixturewas stirred at room temperature for 15 hours. The reaction mixture wasconcentrated under reduced pressure, trifluoroacetic acid (10 mL) wasadded to the obtained residue, and the mixture was stirred at roomtemperature for 1 hour. Trifluoroacetic acid was evaporated underreduced pressure to give a residue. Water (5 mL) and acetonitrile (2 mL)were added to the obtained residue, and the mixture was stirredovernight and purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givetrifluoroacetic acid salt of the title compound.

To the obtained trifluoroacetic acid salt were added 0.1N hydrochloricacid (3.6 mL) and water (10 mL), and the mixture was freeze-dried togive the title compound (162 mg, 0.30 mmol, 38%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.62 (2H, br), 9.30 (2H, br), 8.64 (1H, d,J=2.1 Hz), 8.26 (1H, dd, J=8.4, 2.1 Hz), 7.94-7.91 (2H, m), 7.14-7.11(1H, m), 4.57-3.77 (3H, m), 3.51-2.92 (6H, m), 1.62-1.51 (2H, m),1.12-1.04 (3H, m).

MS (ESI) m/z 493 (M+H)+

Example 29 Synthesis of3-[5-(4-amidino-2-bromophenoxycarbonyl)thiophen-2-yl]-2-methylpropionicacid trifluoroacetic acid salt (B-16)

M-9 (33 mg, 0.10 mmol), M-4 (27 mg, 0.10 mmol), and WSC hydrochloride(21 mg, 0.11 mmol) were dissolved in pyridine (1.0 mL), and the mixturewas stirred overnight and concentrated under reduced pressure.Trifluoroacetic acid (1.5 mL) was added to the residue, and the mixturewas stirred for 30 minutes and concentrated under reduced pressure. Theobtained residue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound (9.0 mg, 0.017 mmol, 17%).

MS (ESI) m/z 411 [M(⁷⁹Br)+H]⁺, 413[M(⁸¹Br)+H]⁺

Example 30 Synthesis of(2E)-3-[4-(4-amidinophenoxycarbonyl)-thiazol-2-yl]-2-methylpropenoicacid trifluoroacetic acid salt (C-1) Step 1. Synthesis of2-formyl-4-thiazolecarboxylic acid ethyl ester

2-(Diethoxymethyl)-4-thiazolecarboxylic acid ethyl ester (2.90 g, 11.8mmol) synthesized according to Bull. Chem. Soc. Jpn., 58, 352 (1985),which is incorporated herein by reference in its entirety, was dissolvedin acetone (37.3 mL), 1N aqueous hydrochloric acid solution (3.73 mL)was added, and the mixture was stirred with heating at 60° C. for 4hours. After evaporation of the solvent, the mixture was worked upaccording to a conventional method to give the title compound as a crudeproduct (2.13 g).

Step 2. Synthesis of3-[4-(ethoxycarboxyl)thiazol-2-yl]-2-methylpropenoic acid tert-butylester

To tetrahydrofuran (38.0 mL) was added 60% sodium hydride (669 mg, 15.3mmol) at 0° C. to give a suspension, a tetrahydrofuran solution (8 mL)of M-13 (4.17 g, 15.7 mmol) was added dropwise thereto, and the mixturewas heated to room temperature. After stirring for 30 minutes, themixture was cooled again to 0° C., and a tetrahydrofuran solution (10mL) of the crude product (2.07 g) obtained in step 1 was added dropwise.Thereafter, the mixture was heated to room temperature and stirred atroom temperature overnight. The mixture was worked up according to aconventional method, and the object product was extracted by columnchromatography (10-15% ethyl acetate/hexane mixed solvent) to give thetitle compound (1.84 g, 6.19 mmol, 2 steps 55%).

¹H-NMR (300 MHz, CDCl₃) δ 8.29 (1H, s), 7.88 (1H, t, J=1.2 Hz), 4.46(2H, q, J=7.2 Hz), 2.30 (3H, d, J=1.2 Hz), 1.54 (9H, s), 1.43 (3H, t,J=7.2 Hz).

MS (ESI) m/z 278 (M+H)+

Step 3. Synthesis of(2E)-3-[4-(4-amidinophenoxycarbonyl)thiazol-2-yl]-2-methylpropenoic acidtrifluoroacetic acid salt (C-1)

Using 3-[4-(ethoxycarboxyl)thiazol-2-yl]-2-methylpropenoic acidtert-butyl ester obtained in step 2 and 4-hydroxybenzamidinehydrochloride and by an operation in the same manner as in Example 16,the title compound was obtained.

¹H-NMR (DMSO-d6) δ 9.36 (2H, br s), 9.09 (2H, br s), 7.93 (2H, d, J=8.6Hz), 7.75 (1H, s), 7.63 (2H, d, J=8.6 Hz), 2.33 (3H, s), 2.30 (1H, s).

MS (ESI) m/z 332 (M+H)+

The compounds A-1, A-2, A-4, A-5, A-7, A-9 to A-11, A-14 to A-21, A-26to A-28, A-30, A-31, A-38, A-40, B-2 to B-5, B-10, B-12, B-18, B-20 toB-24, C-2, and C-3 shown in the following Table 2 were each synthesizedusing M-1 to M-16 and commercially available reagents and by anoperation in the same manner as in the above-mentioned Example 19.Furthermore, B-18 was converted to a salt according to Example 28, step2, and hydrochloride thereof was also obtained (B-18 hydrochloride).

The compounds A-8, A-33, A-34, A-37, B-1, B-8, B-9, B-17, and B-24 shownin the following Table 2 were each synthesized using M-1 to M-16 andcommercially available reagents and by an operation in the same manneras in the above-mentioned Example 17.

The compounds B-13 to B-15 shown in the following Table 2 were eachsynthesized using M-1 to M-16 and commercially available reagents and byan operation in the same manner as in the above-mentioned Example 28.

Example 31 Synthesis of3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2S-methylpropionic acidtrifluoroacetic acid salt (A-41) Step 1. Optical resolution of5-(2-tert-butoxycarbonylpropyl)furan-2-carboxylic acid methyl ester

5-(2-tert-Butoxycarbonylpropyl)furan-2-carboxylic acid methyl ester (303mg, 1.13 mmol) synthesized in Example 11, step 1 was optically resolvedby high performance liquid chromatography using a chiral column(CHIRALCEL (registered trademark) OD, 20 mm×250 mm,2-propanol:n-hexane=1:99, 1 mL/minute) to give respective opticallyactive forms (S form: 105 mg, R form: 131 mg).

Step 2. Synthesis of3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2S-methylpropionic acidtrifluoroacetic acid salt (A-41)

The optically active S form (105 mg, 0.39 mmol) obtained in step 1 wasdissolved in ethanol (1.3 mL), 1N aqueous lithium hydroxide solution (1mol/L, 0.47 mL, 0.47 mmol) was added, and the mixture was stirred atroom temperature for 4 hours. 1N Hydrochloric acid (0.47 mL) was addedto the reaction mixture, and the mixture was concentrated under reducedpressure. 0.5N Hydrochloric acid and ethyl acetate were added to theobtained residue, the organic layer was extracted, and the aqueous layerwas extracted three times with ethyl acetate. The organic layers werecollected, washed with saturated brine, and dried by dehydration withsodium sulfate. After filtration, the solvent of the filtrate wasevaporated under reduced pressure.

To the obtained residue were added 4-amidinophenol hydrochloride (88 mg,0.51 mmol) and WSC hydrochloride (112 mg, 0.59 mmol), and the mixturewas dissolved in pyridine (1.5 m11). After stirring at room temperatureovernight, the reaction mixture was concentrated under reduced pressure,the obtained residue was dissolved in trifluoroacetic acid (containing5% water, 1.5 ml), and the mixture was stirred at room temperature for 2hours. The reaction mixture was concentrated under reduced pressure, andthe obtained residue was purified by high performance liquidchromatography (acetonitrile-water, each containing 0.1% trifluoroaceticacid, 5-35%) to give the title compound (90.0 mg, 0.209 mmol, 53%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.08 (2H, br s), 7.90 (2H,dd, J=6.9, 1.8 Hz), 7.61-7.49 (3H, m), 6.52 (1H, d, J=3.6 Hz), 3.15-2.98(1H, m), 2.90-2.70 (2H, m), 1.14 (3H, d, J=6.9 Hz).

MS (ESI) m/z 317 (M+H)+

Example 32 Synthesis of3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2R-methylpropionic acidtrifluoroacetic acid salt (A-42)

The optically active R form (130 mg, 0.48 mmol) obtained in Example 31,step 1 was dissolved in ethanol (1.0 mL), 1N aqueous lithium hydroxidesolution (1 mol/L, 0.73 mL, 0.73 mmol) was added, and the mixture wasstirred at room temperature for 2 hours. 1N Hydrochloric acid (0.73 mL)was added to the reaction mixture, and the mixture was concentratedunder reduced pressure. 0.5N Hydrochloric acid and ethyl acetate wereadded to the obtained residue, the organic layer was extracted, and theaqueous layer was extracted three times with ethyl acetate. The organiclayers were collected, washed with saturated brine, and dried bydehydration with sodium sulfate. After filtration, the solvent of thefiltrate was evaporated under reduced pressure.

To the obtained residue were added 4-amidinophenol hydrochloride (108mg, 0.62 mmol) and WSC hydrochloride (138 mg, 0.72 mmol), and themixture was dissolved in pyridine (1.6 mL). After stirring at roomtemperature overnight, the reaction mixture was concentrated underreduced pressure, the obtained residue was dissolved in trifluoroaceticacid (containing 5% water, 1.6 mL), and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure and the obtained residue was purified by highperformance liquid chromatography (acetonitrile-water, each containing0.1% trifluoroacetic acid, 5-35%) to give the title compound (112 mg,0.260 mmol, 54%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.08 (2H, br s), 7.90 (2H,dd, J=6.9, 1.8 Hz), 7.61-7.49 (3H, m), 6.52 (1H, d, J=3.6 Hz,),3.15-2.98 (1H, m), 2.90-2.70 (2H, m), 1.14 (3H, d, J=6.9 Hz).

MS (ESI) m/z 317 (M+H)+

Example 33 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2S-methylpropionyl}-L-asparticacid trifluoroacetic acid salt (A-43)

A-41 (31 mg, 0.072 mmol) was dissolved in thionyl chloride (500 μL), andthe mixture was stirred at 70° C. for 20 minutes. Thionyl chloride wasevaporated under reduced pressure, and the obtained residue andL-aspartic acid di-tert-butyl ester hydrochloride (30.4 mg, 0.11 mmol)were dissolved in dichloromethane (350 μL). Pyridine (150 μL) was added,and the mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure, trifluoroacetic acid(500 μL) was added to the obtained residue, and the mixture was stirredat room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure and the obtained residue waspurified by high, performance liquid chromatography (acetonitrile-water,each containing 0.1% trifluoroacetic acid, 5-35%) to give the titlecompound (32 mg, 0.059 mmol, 81%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.10 (2H, br 5), 8.32 (1H,d, J=8.7 Hz), 7.90 (2H, d, J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz), 7.50 (1H,d, J=3.3 Hz), 6.46 (1H, d, J=3.3 Hz), 4.59-4.49 (1H, m), 3.08-2.47 (5H,m), 1.07 (3H, d, J=5.4 Hz).

MS (ESI) m/z 432 (M+H)+

Example 34 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2R-methylpropionyl}-L-asparticacid trifluoroacetic acid salt (A-44)

A-42 (30.8 mg, 0.072 mmol) was dissolved in thionyl chloride (500 μL),and the mixture was stirred at 70° C. for 20 minutes. Thionyl chloridewas evaporated under reduced pressure, and the obtained residue andL-aspartic acid di-tert-butyl ester hydrochloride (30.3 mg, 0.11 mmol)were dissolved in dichloromethane (350 μL). Pyridine (150 μL) was added,and the mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure, trifluoroacetic acid(500 μL) was added to the obtained residue, and the mixture was stirredat room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by high performance liquid chromatography (acetonitrile-water,each containing 0.1% trifluoroacetic acid, 5-35%) to give the titlecompound (33 mg, 0.061 mmol, 85%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.09 (2H, br s), 8.36 (1H,d, J=8.4 Hz), 7.90 (2H, d, J=8.7 Hz), 7.55 (2H, d, J=8.7 Hz), 7.51 (1H,d, J=3.6 Hz), 6.50 (1H, d, J=3.6 Hz), 4.57-4.45 (1H, m), 3.05-2.42 (511,m), 1.05 (3H, d, J=6.6 Hz).

MS (ESI) m/z 432 (M+H)+

Example 35 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2S-methylpropionyl}-D-asparticacid trifluoroacetic acid salt (A-45)

A-41 (31 mg, 0.072 mmol) was dissolved in thionyl chloride (500 μL), andthe mixture was stirred at 70° C. for 20 minutes. Thionyl chloride wasevaporated under reduced pressure, and the obtained residue andD-aspartic acid dibenzyl ester tosylate (56.7 mg, 0.12 mmol) weredissolved in dichloromethane (350 μL). Pyridine (150 μL) was added, andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was dissolved in ethanol (1 mL). 10% Palladium/carbon (5 mg) wasadded, and the mixture was stirred at room temperature overnight under ahydrogen atmosphere. After completion of the reaction, palladium/carbonwas removed by celite filtration. The solvent was evaporated underreduced pressure, and the obtained residue was purified by highperformance liquid chromatography (acetonitrile-water, each containing0.1% trifluoroacetic acid, 5-45%) to give the title compound (8.0 mg,0.015 mmol, 19%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.09 (2H, br s), 8.36 (1H,d, J=8.4 Hz), 7.90 (2H, d, J=8.7 Hz), 7.55 (2H, d, J=8.7 Hz), 7.51 (1H,d, J=3.6 Hz), 6.50 (1H, d, J=3.6 Hz), 4.57-4.45 (1H, m), 3.05-2.42 (5H,m), 1.05 (3H, d, J=6.6 Hz).

MS (ESI) m/z 432 (M+H)+

Example 36 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2R-methylpropionyl}-D-asparticacid trifluoroacetic acid salt (A-46)

A-42 (34.4 mg, 0.080 mmol) was dissolved in thionyl chloride (500 μL),and the mixture was stirred at 70° C. for 20 minutes. Thionyl chloridewas evaporated under reduced pressure, and the obtained residue andD-aspartic acid dibenzyl ester tosylate (58.2 mg, 0.12 mmol) weredissolved in dichloromethane (350 μL). Pyridine (150 μL) was added, andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was dissolved in ethanol (1 mL). 10% Palladium/carbon (5 mg) wasadded, and the mixture was stirred at room temperature overnight under ahydrogen atmosphere. After completion of the reaction, palladium/carbonwas removed by celite filtration. The solvent was evaporated underreduced pressure, and the obtained residue was purified by highperformance liquid chromatography (acetonitrile-water, each containing0.1% trifluoroacetic acid, 5-35%) to give the title compound (33.0 mg,0.061 mmol, 76%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.10 (2H, br s), 8.32 (1H,d, J=8.7 Hz), 7.90 (2H, d, J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz), 7.50 (1H,d, J=3.3 Hz), 6.46 (1H, d, J=3.3 Hz), 4.59-4.49 (1H, m), 3.08-2.47 (5H,m), 1.07 (3H, d, J=5.4 Hz).

MS (ESI) m/z 432 (M+H)+

Example 37 Synthesis ofN-(3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2R-methylpropionyl)-L-asparticacid trifluoroacetic acid salt (B-25) Step 1. Synthesis of(2R)-5-(2-tert-butoxycarbonylpropyl)thiophene-2-carboxylic acid

Using 5-(2-tert-butoxycarbonylpropyl)thiophene-2-carboxylic acid methylester obtained as an intermediate of Example 13, and in the same manneras in Example 31, optical resolution was performed. The obtained(2R)-5-(2-tert-acid methyl ester (0.18 g, 0.63 mmol) was suspended inmethanol (1.6 mL) and tetrahydrofuran (1.6 mL), 1N aqueous lithiumhydroxide solution (1.6 mL) was added, and the mixture was stirredovernight. 1N Hydrochloric acid (2 mL) was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure to give the title compound (0.17g).

MS (ESI) m/z 271 (M+H)+

Step 2. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2R-methylpropionyl}-L-asparticacid trifluoroacetic acid salt (B-25)

The obtained (2R)-5-(2-tert-butoxycarbonylpropyl)-thiophene-2-carboxylicacid (0.17 g, 0.66 mmol), 4-amidino-2-fluorophenol hydrochloride (0.27g, 0.99 mmol), and WSC hydrochloride (0.82 g, 1.31 mmol) were dissolvedin pyridine, and the mixture was stirred for 2 hours. Trifluoroaceticacid (5 mL) was added, and the mixture was stirred for 20 minutes. Thesolvent was evaporated under reduced pressure, purified by highperformance liquid chromatography and freeze-dried to give a white solid(75 mg). The obtained white solid (30 mg, 0.06 mmol), L-aspartic aciddi-tert-butyl ester hydrochloride (20 mg, 0.07 mmol), and WSChydrochloride (35 mg, 0.18 mmol) were dissolved in pyridine (3 mL), andthe mixture was stirred for 3 hours. The solvent was evaporated underreduced pressure, trifluoroacetic acid (3 mL) was added, and the mixturewas stirred for 20 minutes. The solvent was evaporated under reducedpressure, and purified by high performance liquid chromatography andfreeze-dried to give the title compound (28 mg).

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.12 (2H, s), 8.32 (1H, d,J=8.0 Hz), 7.93 (2H, m), 7.74 (2H, m), 7.09 (1H, d, J=3.6 Hz), 4.50 (1H,m), 3.16 (1H, dd, J=14.8, 7.6 Hz), 2.90 (1H, dd, J=14.8, 6.4 Hz),2.75-2.65 (2H, m), 2.55 (1H, dd, J=8.4, 1.2 Hz), 1.05 (3H, d, J=6.8 Hz).

MS (ESI) m/z 466 (M+H)+

Example 38 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2R-isobutylpropionyl}-L-asparticacid trifluoroacetic acid salt (B-26) Step 1. Synthesis of2-(diethylphosphono)-4-methylpentanoic acid tert-butyl ester (M-17)

Using isobutyl bromide instead of ethyl iodide and in the same manner asin Example 7, the compound was synthesized.

¹H-NMR (300 MHz, DMSO-d6) δ 4.08-3.98 (4H, m), 2.85 (1H, ddd, J=22.8,11.4, 3.3 Hz), 1.85-1.75 (1H, m), 1.60-1.45 (2H, m), 1.50 (9H, s), 1.22(6H, m), 0.88 (6H, d, J=7.5 Hz).

MS (ESI) m/z 309 (M+H)+

Step 2. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2R-isobutylpropionyl}-L-asparticacid trifluoroacetic acid salt (B-26)

Using M-17 obtained in step 1 and in the same manner as in Examples 12,13 and 37, the title compound was synthesized.

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.15 (2H, s), 8.39 (1H, d,J=8.0 Hz), 7.93 (2H, m), 7.75 (2H, m), 7.10 (1H, d, J=4.0 Hz), 4.51 (1H,m), 3.07 (1H, dd, J=14.8, 8.0 Hz), 2.92 (1H, dd, J=14.8, 6.4 Hz),2.80-2.65 (2H, m), 2.55 (1H, m), 1.50 (2H, m), 1.13 (1H, m), 0.80 (6H,m).

MS (ESI) m/z 508 (M+H)+

Example 39 Synthesis of5-{2-methyl-2-[(2-phenylethyl)-carbamoyl]ethyl}furan-2-carboxylic acid4-amidinophenyl ester trifluoroacetic acid salt (A-47)

A-6 (50 mg, 0.12 mmol), phenethylamine (17 mg, 0.14 mmol), and WSChydrochloride (46 mg, 0.24 mmol) were dissolved in pyridine (2 mL), andthe mixture was stirred at room temperature for 2 hours. The solvent wasevaporated under reduced pressure and the residue was purified by highperformance liquid chromatography to give the title compound (31 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 9.32 (2H, s), 9.00 (2H, s), 8.00 (1H, t,J=5.4 Hz), 7.87 (2H, d, J=8.7 Hz), 7.52 (2H, m), 7.30-7.10 (6H, m), 6.40(1H, d, J=3.3 Hz), 3.30-3.20 (2H, m), 3.00-2.90 (1H, m), 2.70-2.60 (4H,m), 1.01 (3H, d, J=6.6 Hz).

MS (ESI) m/z 420 (M+H)+

Example 40 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-methylpropanoyl}nipecoticacid trifluoroacetic acid salt (A-52)

A-6 (30 mg, 0.07 mmol), nipecotic acid tert-butyl ester (13 mg, 0.07mmol), and WSC hydrochloride (63 mg, 0.33 mmol) were dissolved inpyridine (3 mL), and the mixture was stirred at room temperatureovernight. The solvent was evaporated under reduced pressure,trifluoroacetic acid (3 mL) was added, and the mixture was stirred atroom temperature for 30 minutes. The solvent was evaporated underreduced pressure and the residue was purified by high performance liquidchromatography to give the title compound (20 mg).

¹H-NMR (400 MHz, DMSO-d6) δ 9.34 (2H, s), 8.98 (2H, s), 7.89 (2H, m),7.55 (3H, m), 6.48 (1H, d, J=3.2 Hz), 3.90-3.80 (2H, m), 3.55-3.25 (2H,m), 3.08-2.98 (2H, m), 2.80-2.70 (2H, m), 2.10-1.20 (4H, m), 1.07 (3H,d, J=6.4 Hz).

MS (ESI) m/z 428 (M+H)+

Example 41 Synthesis ofN-{3-[5-(4-amidino-2-methoxyphenoxycarbonyl)furan-2-yl]-propanoyl}-L-asparticacid trifluoroacetic acid salt (A-53) Step 1. Synthesis of4-amidino-2-methoxyphenol hydrochloride

To 3-methoxy-4-hydroxybenzonitrile (2.0 g, 13.4 mmol) were added ethanol(3 mL) and 4N hydrochloric acid/1,4-dioxane (27 mL), and the mixture wasstirred at room temperature overnight. The solvent was evaporated underreduced pressure and the residue was dissolved in ethanol (50 mL).Ammonium carbonate (6.4 g, 67 mmol) was added, and the mixture wasstirred at room temperature overnight. The solvent was evaporated underreduced pressure, water was added and the mixture was freeze-dried togive the title compound (1.82 g).

¹H-NMR (400 MHz, DMSO-d6) δ 9.40-8.70 (5H, br s), 7.46 (1H, d, J=2.4Hz), 7.40 (1H, dd, J=8.4, 2.4 Hz), 6.97 (1H, d, J=8.4 Hz), 3.86 (3H, s).

MS (ESI) m/z 167 (M+H)+

Step 2. Synthesis of 5-(2-tert-butoxycarbonylethenyl)-furan-2-carboxylicacid benzyl ester

A solution of diethylphosphonoacetic acid tert-butyl ester (1.54 g, 6.09mmol) in tetrahydrofuran (3 mL) was added dropwise to a suspension of60% sodium hydride (0.19 g, 4.87 mmol) in tetrahydrofuran (50 mL) withstirring at 0° C. After stirring at room temperature for 20 minutes, asolution of 5-formyl-2-furancarboxylic acid benzyl ester (1.0 g, 4.06mmol) in tetrahydrofuran (3 mL) was added, and the mixture was stirredat room temperature for 1 hour. The mixture was worked up according to aconventional method, and the object product was extracted by columnchromatography (10-30% ethyl acetate/hexane mixed solvent) to give thetitle compound (1.17 g).

¹H-NMR (400 MHz, CDCl₃) δ 7.45-7.35 (5H, m), 7.32 (1H, d, J=16.0 Hz),7.20 (1H, d, J=3.6 Hz), 6.62 (1H, d, J=3.6 Hz), 6.49 (1H, d, J=16.0 Hz),5.35 (2H, s), 1.50 (9H, s).

Step 3. Synthesis of 5-(2-tert-butoxycarbonylethyl)-furan-2-carboxylicacid (M-22)

5-(2-tert-Butoxycarbonylethenyl)furan-2-carboxylic acid benzyl ester(0.97 g, 2.80 mmol) was dissolved in methanol (50 mL), 10%palladium/carbon (0.1 g) was added, and the mixture was stirred at roomtemperature for 2 hours under a hydrogen atmosphere. After completion ofthe reaction, palladium/carbon was removed by celite filtration, and thesolvent was evaporated under reduced pressure to give the title compound(0.66 g).

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J=3.6 Hz), 6.22 (1H, d, J=3.6Hz), 3.01 (2H, t, J=7.6 Hz), 2.63 (2H, t, J=7.6 Hz), 1.44 (9H, s).

MS (ESI) m/z 241 (M+H)+

Step 4. Synthesis ofN-{3-[5-(4-amidino-2-methoxyphenoxycarbonyl)furan-2-yl]-propanoyl}-L-asparticacid trifluoroacetic acid salt (A-53)

4-Amidino-2-methoxyphenol hydrochloride (63 mg, 0.31 mmol) obtained instep 1, M-22 (50 mg, 0.21 mmol) and WSC hydrochloride (80 mg, 0.42 mmol)were dissolved in pyridine, and the mixture was stirred for 1 hour. Thesolvent was evaporated, and the residue was purified by high performanceliquid chromatography to give a white solid (39 mg). The obtained whitesolid (20 mg), L-aspartic acid di-tert-butyl ester hydrochloride (20 mg,0.07 mmol), and WSC hydrochloride (20 mg, 0.10 mmol) were dissolved inpyridine (3 mL), and the mixture was stirred overnight. The solvent wasevaporated under reduced pressure, trifluoroacetic acid (3 mL) wasadded, and the mixture was stirred for 30 minutes. The solvent wasevaporated under reduced pressure, and the residue was purified by highperformance liquid chromatography and freeze-dried to give the titlecompound (19 mg).

¹H-NMR (400 MHz, DMSO-d6) δ 9.35 (2H, s), 9.01 (2H, s), 8.37 (1H, d,J=8.0 Hz), 7.57 (1H, d, J=2.0 Hz), 7.52-7.44 (3H, m), 6.47 (1H, d, J=2.0Hz), 4.55 (1H, m), 3.88 (3H, s), 2.97 (2H, t, J=7.6 Hz), 2.68-2.55 (4H,m).

MS (ESI) m/z 448 (M+H)+

Example 42 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-propanoyl}-N-(2-carboxyethyl)-glycinetrifluoroacetic acid salt (A-54) Step 1. Synthesis ofN-(2-carboxyethyl)glycine di-tert-butyl ester hydrochloride (M-20)

β-Alanine tert-butyl ester hydrochloride (1.0 g, 5.5 mmol) was dissolvedin dichloromethane (10 mL), triethylamine (1.52 mL, 11.1 mmol) andbromoacetic acid tert-butyl ester (0.57 g, 2.9 mmol) were added, and themixture was stirred for 2 hours. The solvent was evaporated, and theresidue was purified by high performance liquid chromatography. To thefraction containing the object product was added 0.1N hydrochloric acid(30 mL), and the mixture was freeze-dried to give the title compound(0.52 g).

¹H-NMR (400 MHz, CDCl₃) δ 3.75 (2H, s), 3.29 (2H, t, J=6.4 Hz), 2.94(2H, d, J=6.4 Hz), 1.51 (9H, s), 1.47 (9H, s).

MS (ESI) m/z 246 (M+H)+

Step 2. Synthesis of(2E)-3-[5-(benzyloxycarbonyl)furan-2-yl]-2-propenoic acid

To 5-(2-tert-butoxycarbonylethenyl)furan-2-carboxylic acid benzyl ester(0.15 g, 0.46 mmol) obtained in Example 41, step 2 was addedtrifluoroacetic acid (3 mL), and the mixture was stirred for 30 minutes.The solvent was evaporated under reduced pressure to give the titlecompound.

¹H-NMR (400 MHz, CDCl₃) δ 7.80 (1H, d, J=15.6 Hz), 7.75 (1H, d, J=3.6Hz), 7.45-7.35 (5H, m), 7.25 (1H, d, J=3.6 Hz), 6.35 (1H, d, J=15.6 Hz),5.34 (2H, s).

Step 3. Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-propanoyl}-N-(2-carboxyethyl)glycinetrifluoroacetic acid salt (A-54)

(2E)-3-[5-(benzyloxycarbonyl)furan-2-yl]-2-propenoic acid (40 mg, 0.15mmol) was suspended in thionyl chloride (4 mL), and the suspension wasstirred at 70° C. for 30 minutes. After evaporation of the solvent,dichloromethane (2 mL), M-20 (42 mg, 0.16 mmol) and triethylamine (42μL, 0.3 mmol) were added, and the mixture was stirred for 30 minutes.After evaporation of the solvent, the residue was purified by silica gelcolumn chromatography. The obtained solid was dissolved in ethanol (5mL), a catalytic amount of 10% palladium/carbon was added, and themixture was stirred at room temperature for 1 hour under a hydrogenatmosphere. The reaction mixture was filtered through celite, and thefiltrate was concentrated under reduced pressure to give a residue (30mg). The obtained residue, 4-hydroxybenzamidine hydrochloride (15 mg,0.09 mmol) and WSC hydrochloride (20 mg, 0.10 mmol) were dissolved inpyridine (3 mL), and the mixture was stirred at room temperatureovernight. After evaporation of the solvent, trifluoroacetic acid (3 mL)was added, and the mixture was stirred for 30 minutes. After evaporationof the solvent, the residue was purified by high performance liquidchromatography and freeze-dried to give the title compound (14 mg).

¹H-NMR (400 MHz, DMSO-d6) δ 9.34 (2H, s), 8.96 (2H, s), 7.89 (2H, dd,J=6.8, 2.0 Hz), 7.54 (3H, m), 6.52 (0.5H, d, J=3.6 Hz), 6.48 (0.5H, d,J=3.6 Hz), 4.23 (1H, s), 3.96 (1H, s), 3.60 (1H, t, J=6.8 Hz), 3.46 (1H,t, J=6.8 Hz), 2.98-2.85 (2H, m), 2.70-2.40 (2H, m).

MS (ESI) m/z 418 (M+H)+

Example 43 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-propionyl}-N-allylglycinetrifluoroacetic acid salt (A-55) Step 1. Synthesis of N-allylglycinetert-butyl ester (M-21)

Allylamine (10 mL, 0.13 mol) was cooled to 0° C., and a solution ofbromoacetic acid tert-butyl ester (1.0 mL, 6.7 mmol) in dichloromethane(10 mL) was slowly added. After stirring at 0° C. for 3 hours, thereaction mixture was concentrated under reduced pressure. The obtainedresidue was dissolved in diethyl ether, washed successively withsaturated aqueous sodium hydrogen carbonate and saturated brine, anddried over anhydrous sodium sulfate. The obtained solution wasconcentrated under reduced pressure to give the title compound as ayellow liquid (1.15 g, 6.7 mmol, 99%).

¹H-NMR (400 MHz, DMSO-d6) δ 5.87 (1H, ddt, J=17.1, 10.2, 6.1 Hz), 5.19(1H, ddt, J=17.1, 3.2, 1.7 Hz), 5.11 (1H, ddt, J=10.2, 3.2, 1.2 Hz),3.29 (2H, s), 3.25 (2H, ddd, J=6.1, 1.7, 1.2 Hz), 1.47 (9H, s).

MS (ESI) m/z 172 (M+H)+

Step 2. Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-propionyl}-N-allylglycinetrifluoroacetic acid salt (A-55)

A-37 (31.5 mg, 0.076 mmol) was dissolved in thionyl chloride (500 μL),and the mixture was stirred at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, M-21 (38.9 mg,0.23 mmol), dichloromethane (300 μL), and pyridine (200 μL) were addedto the obtained residue, and the mixture was stirred at room temperaturefor 25 minutes. The reaction mixture was concentrated under reducedpressure, trifluoroacetic acid (containing 5% water, 500 μL) was addedto the obtained residue, and the mixture was stirred at room temperaturefor 35 minutes. The reaction mixture was concentrated under reducedpressure, and the obtained residue was purified by high performanceliquid chromatography (acetonitrile-water, each containing 0.1%trifluoroacetic acid, 5-35%) to give the title compound (28.3 mg, 0.056mmol, 74%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.35 (1H, br s), 9.26-9.02 (2H, m),7.95-7.86 (2H, m), 7.58-7.51 (2H, m), 6.52-6.47 (3H, m), 5.94-5.62 (1H,m), 5.23-5.03 (2H, m), 4.13-3.88 (4H, m), 3.04-2.91 (2H, m), 2.83-2.65(2H, m).

MS (ESI) m/z 400 (M+H)+

Example 44 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propanoyl}-L-asparticacid trifluoroacetic acid salt (B-32) Step 1. Synthesis of5-(2-tert-butoxycarbonylethyl)-thiophene-2-carboxylic acid benzyl ester

Using 5-formyl-2-thiophenecarboxylic acid benzyl ester and in the samemanner as in Example 12, the title compound was synthesized.

¹H-NMR (400 MHz, CDCl₃) δ 7.72 (1H, d, J=4.0 Hz), 7.61 (1H, d, J=16.0Hz), 7.43-7.30 (5H, m), 7.18 (1H, d, J=4.0 Hz), 6.28 (1H, J=16.0 Hz),5.38 (2H, s), 1.52 (9H, s).

Step 2. Synthesis of5-(2-tert-butoxycarbonylethyl)-thiophene-2-carboxylic acid (M-23)

The compound (0.5 g, 1.45 mmol) obtained in step 1 was dissolved inmethanol (5 mL) and chloroform (0.5 mL), palladium hydroxide (0.1 g) wasadded, and the mixture was stirred at room temperature overnight under ahydrogen atmosphere. The reaction mixture was filtered through celite,and the solvent was evaporated under reduced pressure to give the titlecompound.

¹H-NMR (300 MHz, DMSO-d6) δ 7.54 (1H, d, J=3.3 Hz), 6.94 (1H, J=3.3 Hz),3.04 (2H, t, J=7.5 Hz), 2.59 (2H, t, J=7.5 Hz), 1.38 (9H, s).

MS (ESI) m/z 257 (M+H)+

Step 3. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propanoyl}-L-asparticacid trifluoroacetic acid salt (B-32)

The title compound was synthesized in the same manner as in Example 38.

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.11 (2H, s), 8.33 (1H, d,J=8.0 Hz), 7.93 (2H, m), 7.73 (2H, m), 7.12 (1H, d, J=3.6 Hz), 4.55 (1H,m), 3.13 (2H, t, J=7.2 Hz), 2.68 (1H, dd, J=12.4, 6.0 Hz), 2.62-2.55(3H, m).

MS (ESI) m/z 452 (M+H)+

Example 45 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propionyl}-N-allylglycinetrifluoroacetic acid salt (B-38)

3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propanoic acidtrifluoroacetic acid salt (38 mg, 0.084 mmol) was dissolved in thionylchloride (500 μL), and the mixture was stirred at room temperature for20 minutes. The reaction mixture was concentrated under reducedpressure, M-21 (18.8 mg, 0.11 mmol), dichloromethane (200 μL) andpyridine (300 μL) were added to the obtained residue, and the mixturewas stirred for 90 minutes. The reaction mixture was concentrated underreduced pressure, trifluoroacetic acid (500 μL) was added to theobtained residue, and the mixture was stirred at room temperature for 30minutes. The reaction mixture was concentrated under reduced pressure,and the obtained residue was purified by high performance liquidchromatography (acetonitrile-water, each containing 0.1% trifluoroaceticacid, 5-35%) to give the title compound (25.5 mg, 0.047 mmol, 55%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.07 (2H, br), 7.96-7.89(2H, m), 7.79-7.70 (2H, m), 7.14 (1H, d, J=3.6 Hz), 5.92-5.62 (1H, m),5.23-5.06 (2H, m), 4.11-3.90 (4H, m), 3.21-3.09 (2H, m), 2.84-2.62 (2H,m).

MS (ESI) m/z 434 (M+H)+

Example 46 Synthesis ofN-(3-[5-(4-amidinophenoxycarbonyl)-thiophen-2-yl]-2-methylpropanoyl)-L-cysteicacid trifluoroacetic acid salt (B-39) Step 1. Synthesis of L-cysteicacid methyl ester hydrochloride (M-18)

L-cysteic acid (300 mg, 1.77 mmol) was dissolved in methanol (12 mL),and thionyl chloride (2.5 mL, 34 mmol) was slowly added at 0° C. Afterstirring at room temperature overnight, the reaction mixture wasconcentrated under reduced pressure, and the obtained residue wassuspended in diisopropyl ether. The suspension was filtered to give thetitle compound as white crystals (291 mg, 1.33 mmol, 75%).

¹H-NMR (300 MHz, DMSO-d6) δ 8.26 (3H, br s), 4.23 (1H, m), 3.72 (3H, s),3.00 (1H, dd, J=14.3, 3.5 Hz), 2.92 (1H, dd, J=14.3, 8.0 Hz).

MS (ESI) m/z 184 (M+H)+

Step 2. Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-thiophen-2-yl]-2-methylpropanoyl}-L-cysteicacid trifluoroacetic acid salt (B-39)

B-6 (10 mg, 0.022 mmol), M-18 (5.9 mg, 0.027 mmol), and WSChydrochloride (6.4 mg, 0.034 mmol) were dissolved in pyridine (1 mL),and the mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure, 4N hydrochloric acid(0.5 mL) and dioxane (0.5 mL) were added to the obtained residue, andthe mixture was stirred at 60° C. for 3 hours. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by high performance liquid chromatography (water-acetonitrile,each containing 0.1% trifluoroacetic acid) to give the title compound(7.4 mg, 0.012 mmol, 56%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.34 (2H, br), 8.89 (2H, br), 8.22-8.18 (1H,m), 7.90-7.86 (3H, m), 7.60-7.56 (2H, m), 7.12-7.11 (1H, m), 4.39-4.33(1H, m), 3.22-2.60 (5H, m), 1.09-1.06 (3H, m).

MS (ESI) m/z 484 (M+H)+

Example 47 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-thiophen-2-yl]-2-methylpropanoyl}aminomethylphosphonicacid trifluoroacetic acid salt (B-40)

Step 1. Synthesis of aminomethylphosphonic acid diethyl esterhydrochloride (M-19).

To a solution of phthalimidomethylphosphonic acid diethyl ester (4.56 g,15.3 mmol) in ethanol (55 mL) was added hydrazine monohydrate (0.89 mL,18.4 mmol), and the mixture was heated under reflux for 5 hours. Theinsoluble material was filtered off, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (dichloromethane/methanol=95/5), and to theobtained oil (1.21 g) were added water (15 mL) and 1N hydrochloric acid(8.0 mL). The mixture was concentrated under reduced pressure andlyophilized to give the title compound (1.48 g, 7.27 mmol, 48%).

¹H-NMR (300 MHz, DMSO-d6) δ 8.50 (3H, br s), 4.12 (4H, m), 3.30 (2H, d,J=13.5 Hz), 1.28 (6H, t, J=7.1 Hz).

MS (ESI) m/z 168 (M+H)+

Step 2. Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-thiophen-2-yl]-2-methylpropanoyl}aminomethylphosphonicacid trifluoroacetic acid salt (B-40)

Using B-6 (10 mg, 0.022 mmol) and M-19 (5.5 mg, 0.027 mmol), and by anoperation in the same manner as in Example 46, the title compound (6.6mg, 0.012 mmol, 55%) was obtained.

¹H-NMR (400 MHz, DMSO-d6) δ 9.45 (2H, br s), 9.20 (2H, br s), 7.98 (1H,br s), 7.85-7.87 (3H, m), 7.50 (1H, br s), 7.08 (1H, d, J=3.0 Hz),3.17-2.75 (5H, m), 1.05 (3H, d, J=6.6 Hz).

MS (ESI) m/z 426 (M+H)+

Example 48 Synthesis of5-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-4-methylpentanoic acidtrifluoroacetic acid salt (A-58) Step 1. Synthesis of5-(1-hydroxy-2-methylprop-2-enyl)furan-2-carboxylic acid benzyl ester

5-Formyl-2-furancarboxylic acid benzyl ester (300 mg, 1.30 mmol) wasdissolved in tetrahydrofuran (12 mL), 2-propenylmagnesium bromide (0.5mol/L tetrahydrofuran solution, 2.6 mL, 1.3 mmol) was added at −78° C.,and the mixture was stirred for 15 minutes. 1N Hydrochloric acid wasadded to the reaction mixture, the mixture was heated to roomtemperature and extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=70/30) to givethe title compound (332 mg, 1.23 mmol, 94%).

¹H-NMR (300 MHz, CDCl₃) δ 7.45-7.33 (5H, m), 7.16 (1H, d, J=3.3 Hz),6.38 (1H, d, J=3.3 Hz), 5.33 (2H, s), 5.21 (1H, s), 5.19 (1H, s), 5.05(1H, s), 1.75 (3H, s).

Step 2. Synthesis of(E)-5-(4-ethoxycarbonyl-2-methylbut-1-enyl)furan-2-carboxylic acidbenzyl ester

To the compound (332 mg, 1.23 mmol) obtained in step 1 were addedtriethyl orthoformate (5.0 mL, 27 mmol) and propionic acid (0.020 mL,0.27 mmol), and the mixture was stirred at 138° C. overnight. Thereaction mixture was purified by silica gel column chromatography(hexane/ethyl acetate=90/10) to give the title compound (149 mg, 0.435mmol, 35%).

¹H-NMR (300 MHz, CDCl₃) δ 7.45-7.35 (5H, m), 7.19 (1H, d, J=3.5 Hz),6.29 (1H, d, J=3.5 Hz), 6.16 (1H, br s), 5.33 (2H, s), 4.14 (2H, q,J=7.2 Hz), 2.51 (4H, br s), 2.05 (3H, d, J=0.9 Hz), 1.25 (3H, t, J=7.2Hz).

MS (ESI) m/z 343 (M+H)+

Step 3. Synthesis of5-(4-ethoxycarbonyl-2-methylbutyl)furan-2-carboxylic acid

To a solution of the compound (149 mg, 0.435 mmol) obtained in step 2 inethanol (3 mL) was added 5% palladium/carbon (15 mg), and the mixturewas stirred under a hydrogen atmosphere for 9 hours. The catalyst wasfiltered off, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound (75 mg, 0.30 mmol, 68%).

¹H-NMR (300 MHz, CDCl₃) δ 7.25 (1H, d, J=3.4 Hz), 6.21 (1H, d, J=3.4Hz), 4.13 (2H, q, J=7.2 Hz), 2.72 (1H, dd, J=15.0, 6.5 Hz), 2.56 (1H,dd, J=15.0, 7.6 Hz), 2.41-2.25 (2H, m), 1.99-1.92 (1H, m), 1.80-1.68(1H, m), 1.57-1.45 (1H, m), 1.25 (3H, t, J=7.2 Hz), 0.93 (3H, d, J=6.7Hz).

MS (ESI) m/z 255 (M+H)+

Step 4. Synthesis of5-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-4-methylpentanoic acid ethylester trifluoroacetic acid salt

To the compound (75 mg, 0.30 mmol) obtained in step 3, 4-amidinophenolhydrochloride (56 mg, 0.32 mmol), and WSC hydrochloride (68 mg, 0.35mmol) was added pyridine (1.5 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and the obtained residue was purified by highperformance liquid chromatography (water-acetonitrile, each containing0.1% trifluoroacetic acid) to give the title compound (80 mg, 0.16 mmol,55%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.14 (4H, br s), 7.88 (2H, d, J=8.7 Hz),7.54 (1H, d, J=3.5 Hz), 7.54 (2H, d, J=8.7 Hz), 6.52 (1H, d, J=3.5 Hz),4.03 (2H, q, J=7.1 Hz), 2.75 (1H, dd, J=15.0, 6.2 Hz), 2.60 (1H, dd,J=15.0, 7.6 Hz), 2.40-2.26 (2H, m), 1.92-1.83 (1H, m), 1.68-1.56 (1H,m), 1.48-1.38 (1H, m), 1.16 (3H, t, J=7.1 Hz), 0.88 (3H, d, J=6.7 Hz).

MS (ESI) m/z 373 (M+H)+

Step 5. Synthesis of5-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-4-methylpentanoic acidtrifluoroacetic acid salt (A-58)

To the compound (77 mg, 0.16 mmol) obtained in step 4 were added 4Nhydrochloric acid (1 mL) and 1,4-dioxane (1 mL), and the mixture wasstirred at 60° C. for 5 hours. The reaction mixture was concentratedunder reduced pressure, and the obtained residue was purified by highperformance liquid chromatography (water-acetonitrile, each containing0.1% trifluoroacetic acid) to give the title compound (33 mg, 0.072mmol, 46%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.23 (4H, br s), 7.88 (2H, d, J=8.7 Hz),7.55 (1H, d, J=3.4 Hz), 7.54 (2H, d, J=8.7 Hz), 6.52 (1H, d, J=3.4 Hz),1.73-2.37 (7H, m), 0.89 (3H, d, J=6.7 Hz).

MS (ESI) m/z 345 (M+H)+

Example 49 Synthesis ofN-{5-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-4-methylpentanoyl}-L-asparticacid trifluoroacetic acid salt (A-59)

To A-58 (30 mg, 0.065 mmol), L-aspartic acid di-tert-butyl esterhydrochloride (17 mg, 0.059 mmol), and WSC hydrochloride (13 mg, 0.065mmol) was added pyridine (1 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, trifluoroacetic acid (1 mL) was added to the obtainedresidue, and the mixture was stirred at room temperature for 2 hours.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound (23 mg, 0.040 mmol, 62%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.33 (2H, br s), 9.10 (2H, br s), 8.10 (1H,d, J=7.6 Hz), 7.89 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 7.55 (1H,d, J=3.5 Hz), 6.53-6.51 (1H, m), 4.50-4.43 (1H, m), 2.75 (1H, dd,J=15.0, 6.2 Hz), 2.69-2.47 (3H, m), 2.25-2.11 (2H, m), 1.88-1.81 (1H,m), 1.63-1.57 (1H, m), 1.41-1.34 (1H, m), 0.89 (3H, d, J=6.6 Hz).

MS (ESI) m/z 460 (M+H)+

Example 50 Synthesis of5-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-4-carboxypentanoic acidtrifluoroacetic acid salt (A-60) Step 1. Synthesis of2-{[5-(benzyloxycarbonyl)furan-2-yl](hydroxy)methyl}prop-2-enoic acidtert-butyl ester

5-Formyl-2-furancarboxylic acid benzyl ester (0.2 g, 0.87 mmol), acrylicacid tert-butyl ester (0.52 mL), and 1,4-diazabicyclo[2.2.2]octane (20mg, 0.18 mmol) were mixed, and the mixture was stirred for 4 days.Excess acrylic acid tert-butyl ester was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.26 g).

¹H-NMR (300 MHz, CDCl₃) δ 7.43-7.32 (5H, m), 7.16 (1H, d, J=3.6 Hz),6.39 (1H, d, J=3.6 Hz), 6.31 (1H, s), 5.85 (1H, s), 5.55 (1H, br s),5.32 (2H, s), 3.40 (1H, m), 1.45 (9H, s).

MS (ESI) m/z 359 (M+H)+

Step 2. Synthesis of5-[5-(benzyloxycarbonyl)furan-2-yl]-4-tert-butoxycarbonyl-4-pentenoicacid ethyl ester

2-{[5-(Benzyloxycarbonyl)furan-2-yl](hydroxy)methyl}prop-2-enoic acidtert-butyl ester (90 mg, 0.25 mmol) was dissolved in ethyl orthoformate(2.0 mL, 10.9 mmol), propanoic acid (B mg, 0.10 mmol) was added, and themixture was stirred at 138° C. for 5 hours. The mixture was purified bysilica gel column chromatography to give the title compound.

MS (ESI) m/z 429 (M+H)+

Step 3. Synthesis of5-[2-(tert-butoxycarbonyl)-5-ethoxy-5-oxopentyl]furan-2-carboxylic acid

5-[5-(Benzyloxycarbonyl)furan-2-yl]-4-tert-butoxycarbonyl-4-pentenoicacid ethyl ester obtained in step 2 was dissolved in ethanol (5 mL), acatalytic amount of 10% palladium/carbon was added, and the mixture wasstirred at room temperature for 1 hour under a hydrogen atmosphere. Thereaction mixture was filtered through celite, and the filtrate wasconcentrated under reduced pressure to give the title compound (82 mg).

MS (ESI) m/z 341 (M+H)+

Step 4. Synthesis of5-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-4-carboxypentanoic acidtrifluoroacetic acid salt (A-60)

Using 5-{2-(tert-butoxycarbonyl)-5-ethoxy-5-oxopentyl}furan-2-carboxylicacid and 4-hydroxybenzamidine hydrochloride, and in the same manner asin Example 46, the title compound was synthesized.

¹H-NMR (300 MHz, DMSO-d6) δ 9.31 (2H, br s), 9.26 (2H, br s), 7.90 (2H,d, J=8.7 Hz), 7.55 (3H, m), 6.51 (1H, d, J=3.6 Hz), 3.00 (1H, m), 2.90(1H, m), 2.73 (1H, m), 2.28 (2H, m), 1.77 (2H, m).

MS (ESI) m/z 375 (M+H)+

Example 51 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-(carboxyethyl)propanoyl}-L-asparticacid trifluoroacetic acid salt (A-61) Step 1. Synthesis of5-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-(2-ethoxycarbonyl)ethylpropanoicacid trifluoroacetic acid salt

5-[2-(tert-Butoxycarbonyl)-5-ethoxy-5-oxopentyl]furan-2-carboxylic acid(82 mg, 0.19 mmol) obtained in Example 50, step 3, 4-hydroxybenzamidinehydrochloride (65 mg, 0.33 mmol), and WSC hydrochloride (92 mg, 0.50mmol) were dissolved in pyridine (3 mL), and the mixture was stirred atroom temperature overnight. The reaction mixture was concentrated underreduced pressure, trifluoroacetic acid (2 mL) was added to the obtainedresidue, and the mixture was stirred at room temperature for 30 minutes.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by high performance liquid chromatographyto give the title compound (11 mg).

MS (ESI) m/z 403 (M+H)+

Step 2. SynthesisN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-(carboxyethyl)propanoyl}-L-asparticacid trifluoroacetic acid salt (A-61)

Using5-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2-(2-ethoxycarbonyl)ethylpropanoicacid trifluoroacetic acid salt and 4-hydroxybenzamidine hydrochlorideand in the same manner as in Example 46, the title compound wassynthesized.

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.06 (2H, s), 8.40 (1H, m),8.89 (2H, d, J=8.7 Hz), 7.55 (2H, d, J=8.7 Hz), 7.50 (1H, d, J=3.3 Hz),6.48 (1H, m), 4.50 (1H, m), 2.95-2.40 (5H, m), 2.22 (2H, m), 1.80-1.60(2H, m).

MS (ESI) m/z 490 (M+H)+

Example 52 Synthesis ofN-{3-[4-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-methylpropanoyl}-L-asparticacid trifluoroacetic acid salt (A-62) Step 1. Synthesis of4-ethoxycarbonylfuran-2-carboxylic acid

3-Furancarboxylic acid ethyl ester (1.4 g, 10.0 mmol) was dissolved inacetic acid (10 mL), bromine (1.6 g, 10.0 mmol) was added, and themixture was stirred overnight. The solvent was evaporated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=80/20). The obtained crude fractionwas dissolved in N,N-dimethylformamide (15 mL), palladium acetate (0.18g, 0.78 mmol), triphenylphosphine (0.41 g, 1.55 mmol), triethylamine(2.2 mL, 15.5 mmol), and water (0.7 mL, 38.8 mmol) were added, and themixture was stirred at 80° C. overnight under a carbon monoxideatmosphere. 1N Hydrochloric acid was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby high performance liquid chromatography to give the title compound(0.47 g).

¹H-NMR (300 MHz, DMSO-d6) δ 8.59 (1H, s), 7.37 (1H, s), 4.26 (2H, q,J=6.9 Hz), 1.28 (3H, t, J=6.9 Hz).

Step 2. Synthesis of 5-hydroxymethyl-3-furancarboxylic acid ethyl ester

4-Ethoxycarbonylfuran-2-carboxylic acid (0.47 g, 2.53 mmol) wasdissolved in tetrahydrofuran (10 mL), triethylamine (0.53 mL, 3.80 mmol)and ethyl chloroformate (0.29 mL, 3.04 mmol) were added at 0° C., andthe mixture was stirred at room temperature for 1 hour. The reactionmixture was filtered through celite, water (0.23 mL, 12.7 mmol) andsodium borohydride (0.19 g, 5.06 mmol) were added to the filtrate, andthe mixture was stirred overnight. 1N Hydrochloric acid was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=50/50) to give the title compound (0.34 g).

¹H-NMR (300 MHz, CDCl₃) δ 7.97 (1H, s), 6.64 (1H, s), 4.62 (2H, s), 4.32(2H, q, J=6.9 Hz), 1.34 (3H, t, J=6.9 Hz).

Step 3. Synthesis 5-formyl-3-furancarboxylic acid ethyl ester

5-Hydroxymethyl-3-furancarboxylic acid ethyl ester (0.34 g, 2.0 mmol)was dissolved in dichloromethane (20 mL), manganese dioxide (1.4 g, 15.9mmol) was added, and the mixture was stirred overnight. The reactionmixture was filtered through celite, and the solvent was evaporatedunder reduced pressure to give the title compound (0.26 g).

¹H-NMR (300 MHz, CDCl₃) δ 9.65 (1H, s), 8.75 (1H, s), 7.80 (1H, s), 4.62(2H, s), 4.27 (2H, q, J=6.9 Hz), 1.30 (3H, t, J=6.9 Hz).

Step 4. Synthesis of 5-(2-tert-butoxycarbonylpropyl)-furan-3-carboxylicacid

M-13 (0.62 g, 2.33 mmol) was added dropwise to a suspension of 60%sodium hydride (0.74 g, 1.86 mmol) in tetrahydrofuran (10 mL) withstirring at 0° C. After stirring at room temperature for 20 minutes, asolution of 5-formyl-3-furancarboxylic acid ethyl ester (0.26 g, 1.55mmol) in tetrahydrofuran (3 mL) was added dropwise at 0° C. Afterstirring at room temperature overnight, the mixture was worked upaccording to a conventional method and purified by column chromatographyto give an oil (0.37 g). The obtained oil was dissolved in ethanol (10mL), 10% palladium/carbon (0.04 g) was added, and the mixture wasstirred at room temperature for hours under a hydrogen atmosphere. Aftercompletion of the reaction, palladium/carbon was removed by celitefiltration, and the solvent was evaporated under reduced pressure. Theobtained residue was dissolved in tetrahydrofuran (1.9 mL) and methanol(0.95 mL), 1N aqueous sodium hydroxide solution (1.9 mL) was added, andthe mixture was stirred overnight. 1N Hydrochloric acid (2.5 mL) wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure to givethe title compound (0.33 g).

¹H-NMR (300 MHz, CDCl₃) δ 8.11 (1H, s), 6.34 (1H, s), 2.85 (1H, dd,J=14.7, 7.5 Hz), 2.70-2.55 (2H, m), 1.33 (9H, s), 1.03 (3H, d, J=6.6Hz).

Step 5. Synthesis ofN-{3-[4-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-methylpropanoyl}-L-asparticacid trifluoroacetic acid salt (A-62)

Using 5-(2-tert-butoxycarbonylpropyl)furan-3-carboxylic acid,4-hydroxybenzamidine, and L-aspartic acid di-tert-butyl esterhydrochloride, and in the same manner as in Example 40, the titlecompound was obtained.

¹H-NMR (300 MHz, DMSO-d6) δ 9.33 (2H, s), 9.05 (2H, s), 8.51 (1H, s),8.24 (0.5H, d, J=7.8 Hz), 8.26 (0.5H, d, J=7.8 Hz), 7.89 (2H, d, J=8.7Hz), 7.52 (2H, d, J=8.7 Hz), 6.61 (0.5H, s), 6.58 (0.5H, s), 4.54 (1H,m), 3.10-2.80 (5H, m), 1.02 (3H, m).

MS (ESI) m/z 432 (M+H)+

Example 53 Synthesis of3-[4-(4-amidino-2-fluorophenoxycarbonyl)furan-2-yl]-2-methylpropanoicacid trifluoroacetic acid salt (A-63)

Using 5-(2-tert-butoxycarbonylpropyl)furan-3-carboxylic acid obtained inExample 52, step 4, and M-11 instead of M-1 and 4-hydroxybenzamidinehydrochloride, and by an operation in the same manner as in Example 16,the title compound was obtained (yield 52%).

¹H-NMR (400 MHz, DMSO-d6) δ 12.35 (1H, br s), 9.41 (2H, br s), 9.18 (2H,br s), 8.62 (1H, d, J=0.8 Hz), 7.92 (1H, dd, J=11.6, 1.6 Hz), 7.76-7.70(2H, m), 6.63 (1H, d, J=0.8 Hz), 2.99 (1H, dd, J=15.0, 6.6 Hz),2.83-2.72 (2H, m), 1.11 (3H, d, J=6.8 Hz).

MS (ESI) m/z 335 (M+H)+

Example 54 Synthesis ofN-{3-[2-(4-amidinophenoxycarbonyl)-furan-4-yl]-2-methylpropanoyl}-L-asparticacid trifluoroacetic acid salt (A-67) Step 1. Synthesis of4-formyl-2-furancarboxylic acid benzyl ester

3-Furfural (0.96 g, 10 mmol) was dissolved in toluene (10 mL),N,N′-dimethylethylenediamine (1.08 mL, 10.0 mmol) and p-toluenesulfonicacid monohydrate (10 mg, 0.11 mmol) were added, and the mixture wasstirred at 105° C. overnight. The solvent was evaporated under reducedpressure and the residue was partitioned between ethyl acetate and 5%aqueous sodium hydrogen carbonate solution. The organic layer was washedwith saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue wasdissolved in tetrahydrofuran (20 mL), 1.54N n-butyllithium/hexanesolution (3 mL) was added dropwise at −78° C., and the mixture wasstirred for 1 hour. Dry ice was added to the reaction mixture, and themixture was stirred at room temperature for 2 hour. The solvent wasevaporated under reduced pressure, N,N-dimethylformamide (10 mL),potassium carbonate (0.55 g, 4.0 mmol), and benzyl bromide (2.04 g, 11.9mmol) were added to the obtained residue, and the mixture was stirred at60° C. overnight. 1N Hydrochloric acid was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound (0.33 g).

¹H-NMR (400 MHz, CDCl₃) δ 9.96 (1H, s), 8.17 (1H, s), 7.52 (1H, s),7.45-7.35 (5H, m), 5.37 (2H, s).

Step 2. Synthesis of 4-(2-tert-butoxycarbonylpropyl)-furan-2-carboxylicacid

The title compound was obtained in the same manner as in Example 52,step 4.

¹H-NMR (400 MHz, DMSO-d6) δ 7.68 (1H, s), 7.10 (1H, s), 2.65-2.55 (3H,m), 1.35 (9H, s), 1.04 (3H, d, J=6.8 Hz).

Step 3. Synthesis ofN-{3-[2-(4-amidinophenoxycarbonyl)-furan-4-yl]-2-methylpropanoyl}-L-asparticacid trifluoroacetic acid salt (A-67)

The title compound was obtained in the same manner as in Example 52,step 5.

¹H-NMR (300 MHz, DMSO-d6) δ 9.33 (2H, s), 8.97 (2H, s), 8.23 (1H, m),7.90-7.80 (3H, m), 7.55 (2H, d, J=8.4 Hz), 7.47 (1H, s), 4.48 (1H, m),3.10-2.90 (3H, m), 2.70-2.50 (2H, m), 1.02 (3H, m).

MS (ESI) m/z 432 (M+H)+

Example 55 Synthesis of3-[4-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2-methylpropanoicacid trifluoroacetic acid salt (B-51) Step 1. Synthesis of5-(2-tert-butoxycarbonylpropyl)-thiophene-3-carboxylic acid

Using 3-thiophenecarboxylic acid methyl ester instead of3-furancarboxylic acid ethyl ester, palladium hydroxide instead ofpalladium/carbon, and lithium hydroxide instead of sodium hydroxide, andin the same manner as in Example 52, step 1 to step 4, the titlecompound was synthesized.

¹H-NMR (300 MHz, CDCl₃) δ 8.03 (1H, d, J=1.2 Hz), 7.25 (1H, d, J=1.2Hz), 3.13 (1H, dd, J=14.8, 8.0 Hz), 2.86 (1H, dd, J=14.8, 6.4 Hz), 2.66(1H, m), 1.45 (9H, s), 1.16 (3H, d, J=7.2 Hz).

MS (ESI) m/z 271 (M+H)+

Step 2. Synthesis of3-[4-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2-methylpropanoicacid trifluoroacetic acid salt (B-51)

Using the compound obtained in step 1 and M-11 instead of M-1 and4-amidinophenol hydrochloride, and by an operation in the same manner asin Example 16, the title compound was obtained (yield 58%).

¹H-NMR (400 MHz, DMSO-d6) δ 12.37 (1H, br s), 9.41 (2H, br s), 9.18 (2H,br s), 8.53 (1H, d, J=1.2 Hz), 7.93 (1H, dd, J=10.6, 1.0 Hz), 7.74-7.75(2H, m), 7.38 (1H, d, J=1.2 Hz), 3.12 (1H, dd, J=15.3, 7.8 Hz), 2.98(1H, dd, J=15.3, 6.0 Hz), 2.71 (1H, m), 1.13 (3H, d, J=7.2 Hz).

MS (ESI) m/z 351 (M+H)+

Example 56 Synthesis ofN-{3-[4-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propanoyl}-L-asparticacid trifluoroacetic acid salt (B-54) Step 1. Synthesis of5-(2-tert-butoxycarbonylethyl)-thiophene-3-carboxylic acid

Using diethylphosphonoacetic acid tert-butyl ester instead of M-13 andin the same manner as in Example 55, step 1, the title compound wassynthesized.

¹H-NMR (300 MHz, DMSO-d6) δ 8.03 (1H, d, J=1.2 Hz), 7.17 (1H, d, J=1.2Hz), 3.00 (2H, t, J=6.4 Hz), 2.58 (2H, t, J=6.4 Hz), 1.38 (9H, s).

MS (ESI) m/z 257 (M+H)+

Step 2. Synthesis ofN-{3-[4-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propanoyl}-L-asparticacid trifluoroacetic acid salt (B-54)

Using the compound obtained in step 1 and in the same manner as inExample 55 and Example 38, the title compound was synthesized.

¹H-NMR (400 MHz, DMSO-d6) δ 9.40 (2H, br s), 9.09 (2H, br s), 8.49 (1H,s), 8.30 (1H, d, J=8.0 Hz), 7.92 (1H, d, J=8.0 Hz), 7.73 (2H, m), 7.38(1H, s), 4.55 (1H, m), 3.07 (2H, t, J=7.6 Hz), 2.70-2.55 (4H, m).

MS (ESI) m/z 452 (M+H)+

Example 57 Synthesis ofN-{4-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]benzoyl}-L-aspartic acidtrifluoroacetic acid salt (A-68)

4-Amidinophenol hydrochloride (50 mg, 0.29 mmol) was dissolved inpyridine (1.5 mL), 4-(5-chlorocarbonylfuran-2-yl)benzoic acid ethylester (81 mg, 0.29 mmol) was added, and the mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and 4N hydrochloric acid/dioxane (2 mL) and water (1mL) were added to the obtained residue. After stirring at 60° C.overnight, the mixture was concentrated under reduced pressure.L-Aspartic acid di-tert-butyl ester hydrochloride (22 mg, 0.078 mmol),WSC hydrochloride (15 mg, 0.078 mmol), and pyridine (1 mL) were added tothe obtained residue, and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,and trifluoroacetic acid (2 mL) was added to the obtained residue. Afterstirring at room temperature for 2 hours, the reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by high performance liquid chromatography (water-acetonitrile,each containing 0.1% trifluoroacetic acid) to give the title compound(17 mg, 0.029 mmol, 10%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.36 (2H, br s), 8.98 (2H, br s), 8.88 (1H,d, J=8.0 Hz), 8.01 (4H, s), 7.93 (2H, d, J=8.8 Hz), 7.79 (1H, d, J=3.6Hz), 7.62 (2H, d, J=8.8 Hz), 7.48 (1H, d, J=3.6 Hz), 4.80-4.75 (1H, m),2.87 (1H, dd, J=16.0, 5.6 Hz), 2.73 (1H, dd, J=16.0, 8.0 Hz).

MS (ESI) m/z 466 (M+H)+

Example 58 Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]benzoyl}-L-aspartic acidtrifluoroacetic acid salt (A-71) Step 1. Synthesis of5-(3-methoxycarbonylphenyl)furan-2-carboxylic acid

To 5-bromofuran-2-carboxylic acid (0.50 g, 2.6 mmol),3-methoxycarbonylphenylboronic acid (0.52 g, 2.9 mmol),tetrakis(triphenylphosphine)palladium (45 mg, 0.039 mmol), and sodiumhydrogen carbonate (0.49 g, 5.9 mmol) were added toluene (3.5 mL),tetrahydrofuran (3.0 mL) and water (3.5 mL), and the mixture was stirredat 90° C. for 2 hours. Water was added to the reaction mixture, and themixture was washed with ethyl acetate. The aqueous layer was acidifiedwith 1N hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure togive the title compound as a pale-yellow powder (0.58 g, 2.3 mmol, 91%).

¹H-NMR (400 MHz, CDCl₃) δ 8.44 (1H, d, J=1.6 Hz), 8.06-8.01 (2H, m),7.54 (1H, dd, J=8.0, 7.6 Hz), 7.42 (1H, d, J=3.6 Hz), 6.89 (1H, d, J=3.6Hz), 3.97 (3H, s).

MS (ESI) m/z 247 (M+H)+

Step 2. Synthesis ofN-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]benzoyl}-L-aspartic acidtrifluoroacetic acid salt (A-71)

To the carboxylic acid obtained by using the compound (100 mg, 0.41mmol) obtained in step 1 and 4-amidinophenol hydrochloride (70 mg, 0.41mmol) instead of B-6 and M-18, and by an operation in the same manner asin Example 46, step 2 were added L-aspartic acid di-tert-butyl esterhydrochloride (114 mg, 0.41 mmol), WSC hydrochloride (93 mg, 0.48 mmol),and pyridine (5 mL), and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,and trifluoroacetic acid (5 mL) was added to the obtained residue. Afterstirring at room temperature for 2 hours, the reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by high performance liquid chromatography (water-acetonitrile,each containing 0.1% trifluoroacetic acid) to give the title compound(15 mg, 0.026 mmol, 6%).

MS (ESI) m/z 466 (M+H)+

Example 59 Synthesis ofO-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-methylpropionyl}-D-malicacid trifluoroacetic acid salt (A-72)

A-6 (34.5 mg, 0.08 mmol) was dissolved in thionyl chloride (500 μL), andthe mixture was stirred at 70° C. for 15 minutes. The reaction mixturewas concentrated under reduced pressure, D-malic acid dibenzyl ester(37.8 mg, 0.12 mmol), dichloromethane (350 μL), and pyridine (150 μL)were added to the obtained residue, and the mixture was stirred at roomtemperature for 25 minutes. The reaction mixture was concentrated underreduced pressure, water was added, and the mixture was freeze-driedovernight. After freeze-drying, palladium/carbon (10 mg) and ethanol (1mL) were added, and the mixture was stirred at room temperature for 3hours. The reaction mixture was filtered through celite to removepalladium/carbon. The filtrate was concentrated under reduced pressure,and the obtained residue was purified by high performance liquidchromatography (acetonitrile-water, each containing 0.1% trifluoroaceticacid, 15-55%) to give the title compound (14.4 mg, 0.026 mmol, 33%).

¹H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.01 (2H, br s), 7.89 (2H,d, J=8.7 Hz), 7.56 (2H, d, J=8.7 Hz), 7.54 (1H, s), 6.61-6.49 (1H, m),5.28-2.19 (1H, m), 3.39-2.60 (5H, m), 1.24-1.04 (3H, m).

MS (ESI) m/z 433 (M+H)+

Example 60 Synthesis ofS-(3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-methylpropionyl)thiomalicacid trifluoroacetic acid salt (A-73) Step 1. Synthesis ofS-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-methylpropionyl}thiomalicacid diethyl ester trifluoroacetic acid salt

A-6 (30 mg, 0.070 mmol) was dissolved in thionyl chloride (500 μL), andthe mixture was stirred at 60° C. for 10 minutes. The reaction mixturewas concentrated under reduced pressure, and thiomalic acid diethylester (21.6 mg, 0.105 mmol), dichloromethane (350 μL), and pyridine (150μL) were added to the obtained residue, and the mixture was stirred atroom temperature for 45 minutes. The reaction mixture was concentratedunder reduced pressure, and the obtained residue was purified by highperformance liquid chromatography (acetonitrile-water, each containing0.1% trifluoroacetic acid, 5-45%) to give the title compound (40 mg,0.065 mmol, 93%).

Step 2. Synthesis ofS-{3-[5-(4-amidinophenoxycarbonyl)-furan-2-yl]-2-methylpropionyl}thiomalicacid trifluoroacetic acid salt (A-73)

ToS-{3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2-methylpropionyl}thiomalicacid diethyl ester trifluoroacetic acid salt (40 mg, 0.065 mmol)obtained in step 1 was added 4N hydrochloric acid/dioxanesolution:water=3:1 (500 μL), and the mixture was stirred at 60° C.overnight. The reaction mixture was concentrated under reduced pressure,and the obtained residue was purified by high performance liquidchromatography (acetonitrile-water, each containing 0.1% trifluoroaceticacid, 10-45%) to give the title compound (5.0 mg, 0.0089 mmol, 14%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.34 (2H, s), 9.15 (2H, s), 7.93-7.87 (2H,m), 7.59-7.51 (3H, m), 6.54 (1H, d, J=3.6 Hz), 4.37-4.28 (1H, m),3.21-3.03 (2H, m), 3.01-2.62 (3H, m), 1.25-1.13 (3H, m).

MS (ESI) m/z 449 (M+H)+

Example 61 Synthesis of(N′-carboxymethyl-{3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2-methylpropane}hydrazido)-aceticacid trifluoroacetic acid salt (A-74) Step 1. Synthesis ofN,N-bis(tert-butoxycarbonylmethyl)-N′-benzyloxycarbonylhydrazine

Benzyloxycarbonylhydrazine (3.0 g, 18 mmol), bromoacetic acid tert-butylester (7.9 mL, 54 mmol), and diisopropylethylamine (6.3 mL, 36 mmol)were dissolved in toluene (30 mL), and the mixture was stirred at 75° C.overnight. After allowing to cool to room temperature, saturated brinewas added, and the mixture was extracted three times withdichloromethane. The extract was dried over anhydrous sodium sulfate andconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (hexane/ethyl acetate=2/1)to give the title compound (5.8 g, 15 mmol, 81%).

¹H-NMR (400 Mz, CDCl₃) δ 7.40-7.20 (5H, m), 7.00 (1H, br s), 5.20 (2H,s), 3.60 (4H, s), 1.45 (18H, s).

MS (ESI) m/z 397 (M+H)+

Step 2. Synthesis of N,N-bis(tert-butoxycarbonylmethyl)-hydrazine

The compound (5.8 g, 15 mmol) obtained in step 1 was dissolved inmethanol (60 mL), 10% palladium/carbon (M) (3.0 g) was added, and themixture was stirred overnight under a hydrogen atmosphere. The reactionmixture was filtered through a filter cell, and the filtrate wasconcentrated. The obtained residue was purified by silica gel columnchromatography (dichloromethane/methanol=9/1) to give the title compound(2.9 g, 11 mmol, 76%).

¹H-NMR (400 Mz, CDCl₃) δ 3.60 (4H, s), 1.45 (18H, s).

MS (ESI) m/z 261 (M+H)+

Step 3. Synthesis of(N′-carboxymethyl-{3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2-methylpropane}hydrazido)-aceticacid trifluoroacetic acid salt (A-74)

To the compound (15 mg, 0.056 mmol) obtained in step 2 were added A-6(20 mg, 0.046 mmol), WSC hydrochloride (13 mg, 0.070 mmol), and pyridine(1 mL), and the mixture was stirred at room temperature overnight. Thereaction mixture was concentrated under reduced pressure, andtrifluoroacetic acid (1 mL) was added to the obtained residue. Afterstirring at room temperature for 2 hours, the reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by high performance liquid chromatography (water-acetonitrile,each containing 0.1% trifluoroacetic acid) to give the title compound(13 mg, 0.023 mmol, 50%).

¹H-NMR (400 MHz, DMSO-d6) δ 12.50 (2H, br s), 9.59 (1H, s), 9.34 (2H, brs), 9.04 (2H, br s), 7.89 (2H, d, J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz),7.49 (1H, d, J=3.5 Hz), 6.45 (1H, d, J=3.5 Hz), 3.70 (4H, s), 2.93 (1H,dd, J=14.6, 7.8 Hz), 2.78-2.70 (2H, m), 1.03 (3H, d, J=6.6 Hz).

MS (ESI) m/z 447 (M+H)+

Example 62 Synthesis ofN-(5-[5-(4-amidinophenoxycarbonyl)-thiophen-2-yl]thiophen-2-ylcarbonyl)-L-asparticacid trifluoroacetic acid salt (B-59) Step 1. Synthesis of2,2′-bithiophene-5,5′-dicarboxylic acid

2,2′-Bithiophene (0.50 g, 3.0 mmol) was dissolved in tetrahydrofuran (10mL), n-butyllithium (2.76 M hexane solution, 2.4 mL, 6.6 mmol) was addedat room temperature under an argon atmosphere, and the mixture wasstirred at 50° C. for 30 minutes. After cooling to room temperature,carbon dioxide was blown into the reaction mixture. The reaction mixturewas concentrated under reduced pressure and the obtained residue waswashed with hexane to give a yellow powder (0.97 g) containing a lithiumsalt of the title compound as a main component. The obtained powder wasdissolved in water and acidified with 1N hydrochloric acid, and theprecipitate was collected by filtration to give the title compound as agreen powder (0.55 g, 2.2 mmol, 72%).

MS (ESI) m/z 255 (M+H)+

Step 2. Synthesis ofN-{5-[5-(4-amidinophenoxycarbonyl)-thiophen-2-yl]thiophen-2-ylcarbonyl}-L-asparticacid trifluoroacetic acid salt (B-59)

To the compound (0.20 g, 0.79 mmol) obtained in step 1, 4-amidinophenolhydrochloride (0.14 g, 0.79 mmol), and WSC hydrochloride (0.18 g, 0.94mmol) was added pyridine (10 mL), and the mixture was stirred at roomtemperature overnight. L-aspartic acid di-tert-butyl ester hydrochloride(0.22 g, 0.79 mmol) and WSC hydrochloride (0.18 g, 0.79 mmol) were addedto the reaction mixture, and the mixture was further stirred at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and trifluoroacetic acid (2 mL) was added to theobtained residue. After stirring at room temperature for 2 hours, thereaction mixture was concentrated under reduced pressure, and theobtained residue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound (1.4 mg, 0.0023 mmol, 0.3%).

MS (ESI) m/z 488 (M+H)+

Example 63 Synthesis ofN-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-ylacetyl]-L-asparticacid trifluoroacetic acid salt (B-60) Step 1. Synthesis of5-tert-butoxycarbonylmethyl-2-thiophenecarboxylic acid

5-Bromomethyl-2-thiophenecarboxylic acid methyl ester (2.6 g, 10.4 mmol)and chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.5 g, 1.02 mmol) weredissolved in formic acid (30 mL), and the mixture was stirred at 75° C.overnight under a carbon monoxide atmosphere. After evaporation of thesolvent, thionyl chloride (10 mL) was added, and the mixture was stirredat 70° C. for 1 hour. The solvent was evaporated under reduced pressure,tert-butanol (10 mL) and triethylamine (2 mL) were added, and themixture was stirred for 30 minutes. After evaporation of the solvent,water was added, and the mixture was extracted with ethyl acetate. Theextract was concentrated and purified by silica gel columnchromatography to give an oil (0.62 g). The oil (0.42 g) was dissolvedin methanol (4.1 mL), 1N aqueous lithium hydroxide solution (4.1 mL) wasadded, and the mixture was stirred for 2 hours. The reaction mixture wasneutralized with 1N hydrochloric acid (5 mL), purified by highperformance liquid chromatography and freeze-dried to give the titlecompound (29 mg).

¹H-NMR (400 MHz, CDCl₃) δ 7.74 (1H, d, J=4.0 Hz), 6.96 (1H, d, J=4.0Hz), 3.78 (2H, s), 1.48 (9H, s).

Step 2. Synthesis of5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-ylacetic acidtrifluoroacetic acid salt

The compound (29 mg, 0.12 mmol) obtained in step 1 and M-11 (34 mg, 0.18mmol) were suspended in pyridine (3 mL), WSC hydrochloride (70 mg, 0.36mmol) was added, and the mixture was stirred for 2 hours. The solventwas evaporated, trifluoroacetic acid (3 mL) was added, and the mixturewas stirred for 15 minutes. The reaction mixture was concentrated underreduced pressure, and the obtained residue was purified by highperformance liquid chromatography (acetonitrile-water, each containing0.1% trifluoroacetic acid, 5-35%) to give the title compound (19 mg).

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.14 (2H, br s), 7.97 (1H,d, J=3.6 Hz), 7.94 (1H, m), 7.80 (2H, m), 7.20 (1H, d, J=3.6 Hz), 4.05(2H, s).

MS (ESI) m/z 323 (M+H)+

Step 3. Synthesis ofN-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-ylacetyl]-L-asparticacid trifluoroacetic acid salt (B-60)

Using the compound obtained in step 2 and in the same manner as inExample 37, the title compound was obtained.

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 8.64 (1H,d, J=4.0 Hz), 7.98 (2H, m), 7.75 (2H, m), 7.14 (1H, d, J=3.6 Hz), 4.55(1H, m), 3.90 (2H, s), 3.08-2.98 (1H, m), 2.70-2.60 (1H, m).

MS (ESI) m/z 438 (M+H)+

Example 64 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiazol-2-yl]-methylpropionyl}-L-asparticacid trifluoroacetic acid salt (C-4) Step 1. Synthesis of5-(tert-butyldimethylsilyloxy)-methylthiazole

5-Hydroxymethylthiazole (5.0 g, 43 mmol), imidazole (7.4 g, 109 mmol),and diisopropylethylamine (14 g, 109 mmol) were dissolved inN,N-dimethylformamide (50 mL), tert-butyldimethylsilyl chloride (13.1 g,87 mmol) was added, and the mixture was stirred at room temperature for20 hours. Ethyl acetate (200 mL) and water (100 mL) were added to thereaction mixture, the mixture was partitioned, and the organic layer waswashed with saturated brine. The organic layer was dried over anhydroussodium sulfate and purified by silica gel column chromatography to givethe title compound.

¹H-NMR (300 MHz, DMSO-d6) δ 8.71 (1H, s), 7.70 (1H, s), 4.90 (2H, s),0.90 (9H, s), 0.08 (6H, s).

Step 2. Synthesis of5-(tert-butyldimethylsilyloxy)-methyl-2-formylthiazole

The compound (4.5 g, 20 mmol) obtained in step 1 was dissolved intetrahydrofuran (30 mL), and 2.5M n-butyllithium/hexane solution (16 mL,40 mmol) was added dropwise at −78° C. The reaction mixture was stirredat −78° C. for 35 minutes, N,N-dimethylformamide (4 mL) was addeddropwise, and the mixture was stirred at −30° C. for 1 hour. Thereaction mixture was neutralized with water and 2N hydrochloric acid,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give the title compound (1.6g).

¹H-NMR (300 MHz, DMSO-d6) δ 9.91 (1H, s), 7.89 (1H, s), 4.95 (2H, s),0.90 (9H, s), 0.10 (6H, s).

Step 3. Synthesis of5-[2-(tert-butoxycarbonyl)-1-propenyl]-2-(tert-butyldimethylsilyloxy)methylthiazole

To a suspension of 60% sodium hydride (0.12 g, 3.0 mmol) intetrahydrofuran (5 mL) was added M-13 (0.92 g, 2.57 mmol) at 0° C., andthe mixture was stirred for 35 minutes. A solution of the compound (0.5g, 2.0 mmol) obtained in step 2 in tetrahydrofuran (20 mL) was added,and the mixture was stirred at room temperature for 2 hours. Ethylacetate (30 mL) and water (5 mL) were added to the reaction mixture, themixture was partitioned, and the organic layer was washed with saturatedbrine. The organic layer was dried over anhydrous sodium sulfate andpurified by silica gel column chromatography to give the title compound(0.68 g).

¹H-NMR (300 MHz, CDCl₃) δ 7.74 (1H, s), 7.70 (1H, s), 4.93 (2H, s), 2.29(3H, s), 1.53 (9H, s), 0.92 (9H, s), 0.11 (6H, s).

Step 4. Synthesis of5-[2-(tert-butoxycarbonyl)propyl]-2-(tert-butyldimethylsilyloxy)methylthiazole

The compound (0.5 g, 1.4 mmol) obtained in step 3 was dissolved inethanol (20 mL), palladium/carbon (0.1 g) was added, and the mixture wasstirred at 50° C. for 20 hours under a hydrogen atmosphere (55 psi). Thereaction mixture was filtered, and the solvent was evaporated underreduced pressure to give the title compound (0.3 g).

¹H-NMR (300 MHz, CDCl₃) δ 7.42 (1H, s), 4.82 (2H, s), 3.32-3.23 (1H, m),3.01-2.91 (1H, m), 2.89-2.80 (1H, m), 1.38 (9H, s), 1.17 (3H, d, J=6.8Hz), 0.87 (9H, s), 0.05 (6H, s).

Step 5. Synthesis of5-[2-(tert-butoxycarbonyl)propyl]-2-formylmethylthiazole

To a solution of n-tetrabutylammonium fluoride (0.39 g, 1.5 mmol) intetrahydrofuran (5 mL) was added a solution of the compound (0.30 g,0.76 mmol) obtained in step 4 in tetrahydrofuran (2 mL), and the mixturewas stirred at room temperature overnight. The solvent was evaporatedunder reduced pressure, and the residue was partitioned between ethylacetate and water. The organic layer was washed with saturated brine.The organic layer was dried over anhydrous sodium sulfate and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give an oil (0.16 g). The obtained oilwas dissolved in dichloromethane (15 mL), manganese dioxide (0.27 g, 3.0mmol) was added, and the mixture was refluxed overnight. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography to give an oil (0.10 g).

¹H-NMR (300 MHz, CDCl₃) δ 9.97 (1H, s), 8.27 (1H, s), 3.42-3.34 (1H, m),3.11-3.03 (1H, m), 2.96-2.89 (1H, m), 1.39 (9H, s), 1.20 (3H, d, J=6.9Hz).

Step 6. Synthesis of5-[2-(tert-butoxycarbonyl)propyl]-thiazole-2-carboxylic acid

To a solution of the compound (1.8 g, 7.0 mmol) obtained in step 5 intert-butanol (27.1 mL) were added water (6.0 mL), 2-methyl-2-butene (3.7g, 52.9 mmol), sodium dihydrogen phosphate (3.1 g, 17.6 mmol), andsodium chlorite (3.2 g, 35.2 mmol), and the mixture was stirred at roomtemperature for 20 minutes. The solvent was evaporated, and the pH wasadjusted to 8-9 with water and sodium hydrogen carbonate solution. Thereaction mixture was washed with ethyl acetate, and the aqueous layerwas adjusted to pH 5-6 with 2N hydrochloric acid. The aqueous layer wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated to give the title compound (1.1 g).

¹H-NMR (300 MHz, CDCl₃) δ 13.44 (1H, br s), 8.21 (1H, s), 3.30-3.20 (1H,m), 3.18-3.03 (1H, m), 2.91-2.84 (1H, m), 1.35 (9H, s), 1.14 (3H, d,J=7.2 Hz).

Step 7. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiazol-2-yl]-methylpropionyl}-L-asparticacid trifluoroacetic acid salt (C-4)

Using the compound obtained in step 6 and in the same manner as inExample 37, the title compound was obtained.

¹H-NMR (400 MHz, DMSO-d6) δ 9.42 (2H, s), 9.16 (2H, s), 8.62 (1H, s),8.36 (1H, m), 7.95 (1H, dd, J=11.0, 2.0 Hz), 7.76 (2H, m), 4.50 (1H, m),3.30 (1H, m), 3.10-2.85 (1H, m), 2.75-2.55 (3H, m), 1.10 (3H, m).

MS (ESI) m/z 467 (M+H)+

Example 65 Synthesis of3-{3-[4-(4-amidinophenoxycarbonyl)-1,3-thiazol-2-yl]-Narboxymethyl)propanamido}propanoicacid trifluoroacetic acid salt (C-5) Step 1. Synthesis of3-[4-(ethoxycarboxyl)thiazol-2-yl]propenoic acid tert-butyl ester

Using 2-formyl-4-thiazolecarboxylic acid ethyl ester obtained in Example30, step 1 and diethylphosphonoacetic acid tert-butyl ester, and in thesame manner as in Example 30, the title compound was obtained.

¹H-NMR (400 MHz, CDCl₃) δ 8.19 (1H, s), 7.75 (1H, d, J=16.0 Hz), 6.64(1H, d, J=16.0 Hz), 4.45 (2H, q, J=6.8 Hz), 1.53 (9H, s), 1.42 (3H, t,J=6.8 Hz).

Step 2. Synthesis of2-[(1E)-2-{[2-(tert-butoxy)-2-oxoethyl][3-(tert-butoxy)-3-oxopropyl]carbamoyl}eth-1-en-1-yl]-1,3-thiazole-4-carboxylicacid ethyl ester

The compound (0.45 g, 1.51 mmol) obtained in step 1 was dissolved intrifluoroacetic acid (10 mL), and the mixture was stirred for 1 hour.The solvent was evaporated to give a white solid (0.36 g). The whitesolid (0.26 g, 1.06 mmol) was dissolved in dichloromethane (15 mL),oxalyl chloride (0.15 mL, 1.75 mmol) and N,N-dimethylformamide (1 drop)were added, and the mixture was stirred for 10 minutes. The solvent wasevaporated under reduced pressure, a solution of M-20 (0.32 g, 1.08mmol) in dichloromethane (10 mL) and pyridine (0.25 mL) were added, andthe mixture was stirred for 2 hours. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 8.21 (0.5H, s), 8.19 (0.5H, s), 7.80 (0.5H, d,J=15.2 Hz), 7.74 (0.5H, d, J=14.8 Hz), 7.39 (0.5H, d, J=15.2 Hz), 7.08(0.5H, d, J=14.8 Hz), 4.43 (2H, m), 4.23 (1H, s), 4.13 (1H s), 3.81 (1H,t, J=6.8 Hz), 3.71 (1H, t, J=6.8 Hz), 2.62 (2H, m), 1.43 (21H, m).

Step 3. Synthesis of2-(2-{[2-(tert-butoxy)-2-oxoethyl][3-(tert-butoxy)-3-oxopropyl]carbamoyl}ethyl)-1,3-thiazole-4-carboxylicacid

The compound (0.4 g, 0.85 mmol) obtained in step 2 was dissolved inmethanol (9 mL) and chloroform (1 mL), palladium hydroxide (0.08 g) wasadded, and the mixture was stirred at room temperature overnight under ahydrogen atmosphere. The reaction mixture was filtered through celite,and the solvent was evaporated. The residue was dissolved in methanol (1mL), 1N aqueous lithium hydroxide solution (1.55 mL) was added, and themixture was stirred for 3 hours. The mixture was neutralized with 1Nhydrochloric acid, and extracted with ethyl acetate. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was purified by high performance liquid chromatography(acetonitrile-water, each containing 0.1% trifluoroacetic acid) to givethe title compound (0.26 g).

¹H-NMR (400 MHz, CDCl₃) δ 8.16 (1H, s), 4.12 (1H, s), 4.02 (1H, s), 3.69(1H, t, J=6.8 Hz), 3.60 (1H, t, J=6.8 Hz), 3.43-3.35 (2H m), 3.01 (1H,t, J=6.8 Hz), 2.77 (1H, t, J=6.8 Hz), 2.58-2.48 (2H, m), 1.45 (18H, m).

Step 4. Synthesis of3-{3-[4-(4-amidinophenoxycarbonyl)-1,3-thiazol-2-yl]-N-(carboxymethyl)propanamido}propanoicacid trifluoroacetic acid salt (C-5)

Using the compound obtained in step 3 and in the same manner as inExample 37, the title compound was obtained.

¹H-NMR (400 MHz, DMSO-d6) δ 9.35 (2H, s), 9.02 (2H, s), 8.72 (1H, s),7.91 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 4.22 (1H, s), 3.97 (1H,s), 3.65-3.30 (4H, m), 2.95 (1H, t, J=6.8 Hz), 2.75 (1H, t, J=6.8 Hz),2.55 (1H, t, J=6.8 Hz), 2.45 (1H, t, J=6.8 Hz).

MS (ESI) m/z 449 (M+H)+

Example 66 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)-3-methylthiophen-2-yl]propanoyl}-L-asparticacid trifluoroacetic acid salt (B-61) Step 1. Synthesis of1,3-dimethyl-2-(3-methylthiophen-2-yl)imidazolidine

2-Formyl-3-methylthiophene (3.0 g, 23.8 mmol) andN,N′-dimethylethylenediamine (2.3 g, 26.2 mmol) were dissolved intoluene (80 mL), and the mixture was stirred at 120° C. overnight. Thesolvent was evaporated under reduced pressure, and the obtained residuewas purified by silica gel column chromatography to give the titlecompound (3.1 g, 15.8 mmol).

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J=5.2 Hz), 6.77 (1H, d, J=5.2Hz), 3.79 (1H, s), 3.40-3.33 (2H, m), 2.60-2.55 (2H, m), 2.25 (9H, s).

Step 2. Synthesis of 5-formyl-4-methylthiophene-2-carboxylic acid benzylester

1,3-Dimethyl-2-(3-methylthiophen-2-yl)imidazolidine (3.1 g, 15.8 mmol)obtained in step 1 was dissolved in tetrahydrofuran (80 mL), 2.76Nn-butyllithium/hexane solution (6.9 mL) was added dropwise at −78° C.,and the mixture was stirred for 30 minutes. Dry ice was added to thereaction mixture, and the mixture was stirred at room temperature for 1hour. The solvent was evaporated under reduced pressure,N,N-dimethylformamide (80 mL), potassium carbonate (6.54 g, 47.4 mmol),and benzyl bromide (8.0 g, 46.8 mmol) were added to the obtainedresidue, and the mixture was stirred at 60° C. for 3 hour. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive the title compound (1.84 g).

¹H-NMR (400 MHz, CDCl₃) δ 10.07 (1H, s), 7.63 (1H, s), 7.45-7.35 (5H,m), 5.35 (2H, s), 2.57 (3H, s).

Step 3. Synthesis of(E)-3-(5-benzyloxycarbonyl-3-methylthiophen-2-yl)-2-propenoic acidtert-butyl ester

A solution of diethylphosphonoacetic acid tert-butyl ester (0.44 g, 1.74mmol) in tetrahydrofuran (3 mL) was added dropwise to a suspension of60% sodium hydride (0.055 g, 1.38 mmol) in tetrahydrofuran (15 mL) withstirring at 0° C. After stirring at room temperature for 30 minutes, asolution of 5-formyl-4-methylthiophene-2-carboxylic acid benzyl ester(0.3 g, 1.15 mmol) obtained in step 2 in tetrahydrofuran (3 mL) wasadded dropwise at 0° C. After stirring at room temperature for 2 hours,the mixture was worked up according to a conventional method, andpurified by silica gel column chromatography to give the title compound(0.35 g).

¹H-NMR (400 MHz, CDCl₃) δ 7.70 (1H, d, J=15.6 Hz), 7.55 (1H, s),7.45-7.35 (5H, m), 6.23 (1H, d, J=15.6 Hz), 5.32 (2H, s), 2.31 (3H, s),1.52 (9H, s).

Step 4. Synthesis of3-(5-hydroxycarbonyl-3-methylthiophen-2-yl)propanoic acid tert-butylester

(E)-3-(5-Benzyloxycarbonyl-3-methylthiophen-2-yl)-2-propenoic acidtert-butyl ester (1.42 g, 4.12 mmol) obtained in step 3 was dissolved inethanol (12 ml), 10% palladium/carbon (142 mg) was added, and themixture was stirred at room temperature overnight under a hydrogenatmosphere. After completion of the reaction, palladium/carbon wasremoved by celite filtration, and the solvent was evaporated underreduced pressure to give the title compound (1.02 g, 3.77 mmol, 92%).

¹H-NMR (400 MHz, CDCl₃) δ 7.48 (1H, s), 2.98 (2H, t, J=7.6 Hz), 2.51(2H, t, J=7.6 Hz), 2.11 (3H, s), 1.43 (9H, s).

Step 5. Synthesis of3-[5-(4-amidino-2-fluorophenoxycarbonyl)-3-methylthiophen-2-yl]propanoicacid trifluoroacetic acid salt

The compound (1.02 g, 3.77 mmol) obtained in step 4, M-11 (1.08 g, 5.66mmol), and WSC hydrochloride (1.45 g, 7.55 mmol) were dissolved inpyridine (10 ml), and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated, and the solvent wasevaporated under reduced pressure. Trifluoroacetic acid (10 mL) wasadded, and the mixture was stirred at room temperature for 1 hour. Thesolvent was evaporated under reduced pressure, and the obtained residuewas purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound (535 mg, 1.15 mmol, 31%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.41 (2H, br s), 9.14 (2H, br s), 7.96-7.89(1H, m), 7.86 (1H, s), 7.77-7.71 (2H, m), 3.05 (2H, t, J=7.2 Hz), 2.61(2H, t, J=7.2 Hz), 2.22 (3H, s).

MS (ESI) m/z 351 (M+H)+

Step 6. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)-3-methylthiophen-2-yl]propanoyl}-L-asparticacid trifluoroacetic acid salt (B-61)

The compound (432 mg, 0.93 mmol) obtained in step 5, aspartic aciddi-tert-butyl ester (393 mg, 1.40 mmol), and WSC hydrochloride (357 mg,1.86 mmol) were dissolved in pyridine (3.0 mL), and the mixture wasstirred at room temperature. The solvent was evaporated under reducedpressure, trifluoroacetic acid (3.0 mL) was added to the residue, andthe mixture was stirred at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound (474 mg, 0.82 mmol, 88%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.40 (2H, br s), 9.11 (2H, br s), 8.29 (1H,d, J=7.2 Hz), 7.92 (1H, d, J=11.2 Hz), 7.84 (1H, s), 7.77-7.71 (2H, m),4.57-4.46 (1H, m), 3.03 (2H, t, J=7.6 Hz), 2.71-2.49 (4H, m), 2.21 (3H,s).

MS (ESI) m/z 466 (M+H)+

Example 67 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propanoyl}-N-allyl-L-asparticacid trifluoroacetic acid salt (B-63) Step 1. Synthesis ofN-allyl-L-aspartic acid di-tert-butyl ester hydrochloride

L-aspartic acid di-tert-butyl ester hydrochloride (1.0 g, 3.5 mmol) wasdissolved in acetonitrile (7 ml), potassium carbonate (0.98 g, 7.1 mmol)and allyl bromide (0.29 mL, 3.4 mmol) were added, and the mixture wasstirred at room temperature overnight. The insoluble material wasremoved by filtration, the filtrate was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=95/5) to give N-allyl-L-asparticacid di-tert-butyl ester (0.50 g, 1.8 mmol).

¹H-NMR (400 MHz, CDCl₃) δ 5.86 (1H, dddd, J=17.2, 10.2, 6.1, 5.9 Hz),5.16-5.21 (1H, m), 5.06-5.10 (1H, m), 3.47 (1H, dd, J=6.8, 5.9 Hz),3.30-3.36 (1H, m), 3.15-3.20 (1H, m), 2.60 (1H, dd, J=15.7, 5.9 Hz),2.51 (1H, dd, J=15.7, 6.8 Hz), 1.47 (9H, s), 1.45 (9H, s).

MS (ESI) m/z 286 (M+H)+

The obtained N-allyl-L-aspartic acid di-tert-butyl ester was dissolvedin acetonitrile (10 mL), and water (17 mL) and 1N hydrochloric acid (1.8mL, 1.8 mmol) were added. The solution was concentrated under reducedpressure and freeze-dried to give the title compound (0.54 g, 1.7 mmol,47%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.25 (2H, br s), 5.84-5.94 (1H, m), 5.48(1H, d, J=17.2 Hz), 5.41 (1H, d, J=9.6 Hz), 4.11 (1H, br s), 3.65 (2H,br s), 2.96 (1H, br d, J=17.8 Hz), 2.86 (1H, dd, J=17.8, 5.8 Hz), 1.45(9H, s), 1.44 (9H, s).

MS (ESI) m/z 286 (M+H)+

Step 2. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propanoyl}-N-allyl-L-asparticacid trifluoroacetic acid salt (B-63)

Using N-allyl-L-aspartic acid di-tert-butyl ester hydrochloride obtainedin step 1, M-11, and M-23, and by an operation in the same manner as inExample 33, the title compound (yield 24%) was obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.56-9.10 (4H, m), 7.98-7.89 (2H, m),7.79-7.70 (2H, m), 718-7.09 (1H, m), 5.95-5.65 (1H, m), 5.46-4.95 (2H,m), 4.61-4.48 (1H, m), 4.18-3.84 (2H, m), 3.71-2.41 (6H, m).

MS (ESI) m/z 492 (M+H)+

Example 68 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropanoyl}-L-asparticacid trifluoroacetic acid salt (B-64) Step 1. Synthesis of5-chloromethylthiophene-2-carboxylic acid tert-butyl ester

5-Formylthiophene-2-carboxylic acid (5.27 g, 33.7 mmol), di-tert-butyldicarbonate (8.1 g, 37.1 mmol), and N,N-dimethylaminopyridine (0.41 g,3.39 mmol) were dissolved in tert-butanol (120 mL) and dichloromethane(40 mL), and the mixture was stirred overnight. The solvent wasevaporated under reduced pressure, and 0.5N aqueous hydrochloric acidsolution was added to the residue, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The obtained residue was dissolved in tetrahydrofuran (100 mL) andmethanol (10 mL), sodium borohydride (1.28 g, 33.7 mmol) was added at 0°C., and the mixture was stirred for 3 hours. The solvent was evaporatedunder reduced pressure, 0.5N aqueous hydrochloric acid solution wasadded to the residue, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The obtainedresidue was dissolved in dichloromethane (100 mL), methanesulfonylchloride (2.87 mL, 37.1 mmol) and diisopropylethylamine (8.9 mL, 51.1mmol) were added at 0° C., and the mixture was stirred for 2 days. Thesolvent was evaporated under reduced pressure, 0.5N aqueous hydrochloricacid solution was added to the residue, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound (7.5 g).

¹H-NMR (400 MHz, DMSO-d6) δ 7.56 (1H, d, J=4.0 Hz), 7.04 (1H, d, J=4.0Hz), 4.75 (2H, s), 1.57 (9H, s).

Step 2. Synthesis of 3-(5-carboxythiophen-2-yl)-2,2-dimethylpropanoicacid

Diisopropylamine (478 μL, 3.40 mmol) was dissolved in tetrahydrofuran(2.0 mL), the mixture was stirred at −78° C. for 15 minutes, and 2.6Nn-butyllithium/hexane solution (1.31 mL, 3.40 mmol) was added dropwise.After dropwise addition, the mixture was stirred at 0° C. for 30minutes, and isobutyric acid (158 μL, 1.70 mmol) was added dropwise at−78° C. After the completion of the dropwise addition, the mixture wasstirred at 0° C. for 20 minutes, 5-chloromethylthiophene-2-carboxylicacid tert-butyl ester (360 mg, 1.55 mmol) dissolved in tetrahydrofuran(1.5 mL) was added at 0° C., and the mixture was stirred at roomtemperature overnight. Ethyl acetate and 1N aqueous hydrochloric acidsolution were added to the reaction mixture, the mixture waspartitioned, and the organic layer was separated. The aqueous layer wasextracted three times with ethyl acetate, and the organic layers wascombined and washed with saturated brine. The organic layer was driedover magnesium sulfate, and the solvent was evaporated to give the titlecompound as a crude product.

Step 3. Synthesis ofN-[3-(5-carboxythiophen-2-yl)-2,2-dimethylpropanoyl]-L-aspartic aciddimethyl ester

The crude product obtained in step 2 was dissolved in thionyl chloride(3.0 mL), and the mixture was stirred at 60° C. for 30 minutes. Thereaction mixture was concentrated under reduced pressure, L-asparticacid dimethyl ester hydrochloride (460 mg, 2.33 mmol), dichloromethane(1.0 mL), and pyridine (2.0 mL) were added to the obtained residue, andthe mixture was stirred at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure, trifluoroacetic acid(3.0 mL) was added to the obtained residue, and the mixture was stirredat room temperature for 5 hours. The reaction mixture was concentratedunder reduced pressure, and the obtained residue was purified by highperformance liquid chromatography (water-acetonitrile, each containing0.1% trifluoroacetic acid) to give the title compound (59.7 mg, 0.16mmol, yield in 4 steps 10%).

MS (ESI) m/z 372 (M+H)+

Step 4. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropanoyl}-L-asparticacid trifluoroacetic acid salt (B-64)

The compound (56 mg, 0.15 mmol) obtained in step 3, M-11 (43.1 mg, 0.23mmol), and WSC hydrochloride (57.8 mg, 0.30 mmol) were dissolved inpyridine (500 μL), and the mixture was stirred at room temperature for 1hour. The solvent was evaporated, and the residue was azeotropicallydistilled with benzene. 4N Hydrochloric acid/1,4-dioxane solution (750μL) and water (250 μL) were added, and the mixture was stirred at 60° C.overnight. The reaction mixture was concentrated under reduced pressure,and the obtained residue was purified by high performance liquidchromatography (acetonitrile-water, each containing 0.1% trifluoroaceticacid, 10-40%) to give the title compound (11 mg, 0.019 mmol, 12%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.41 (2H, br s), 9.10 (2H, br s), 7.96-7.89(3H, m), 7.79-7.71 (2H, m), 7.07 (1H, d, J=4.0 Hz), 4.57 (1H, dt, J=7.2,6.8 Hz), 3.13 (2H, s), 2.76 (1H, dd, J=16.4, 6.8 Hz), 2.58 (1H, dd,J=16.4, 6.8 Hz), 1.14 (3H, s), 1.13 (3H, s).

MS (ESI) m/z 480 (M+H)+

Compound B-37 shown in the following Table 2 was synthesized using M-20and by an operation in the same manner as in the above-mentioned Example18.

The compounds A-22, A-23, A-24, A-25, A-66, B-33, B-35, B-52, and B-53shown in the following Table 2 were each synthesized using M-1 to M-23and commercially available reagents and by an operation in the samemanner as in the above-mentioned Examples 33 and 34.

Compound B-36 shown in the following Table 2 was synthesized using M-1to M-23 and commercially available reagents and by an operation in thesame manner as in the above-mentioned Example 35.

The compounds B-27, B-28, and B-29 shown in the following Table 2 wereeach synthesized using M-1 to M-23 and commercially available reagentsand by an operation in the same manner as in the above-mentioned Example38.

The compounds A-48, A-49, A-50, and A-51 shown in the following Table 2were each synthesized using M-1 to M-23 and commercially availablereagents and by an operation in the same manner as in theabove-mentioned Example 39.

The compounds B-30, B-31, and B-34 shown in the following Table 2 wereeach synthesized using M-1 to M-23 and commercially available reagentsand by an operation in the same manner as in the above-mentioned Example40.

Compound B-45 shown in the following Table 2 was synthesized using M-1to M-23 and commercially available reagents and by an operation in thesame manner as in the above-mentioned Examples 44 and 46.

Compound B-46 shown in the following Table 2 was synthesized using M-1to M-23 and commercially available reagents and by an operation in thesame manner as in the above-mentioned Examples 44 and 47.

The compounds A-57, B-41, and B-44 shown in the following Table 2 wereeach synthesized using M-1 to M-23 and commercially available reagentsand by an operation in the same manner as in the above-mentioned Example46.

The compounds A-56, B-42, and B-43 shown in the following Table 2 wereeach synthesized using M-1 to M-23 and commercially available reagentsand by an operation in the same manner as in the above-mentioned Example47.

The compounds A-64 and A-65 shown in the following Table 2 were eachsynthesized using M-1 to M-23 and commercially available reagents and byan operation in the same manner as in the above-mentioned Examples 47and 52.

Compound A-70 shown in the following Table 2 was synthesized using M-1to M-23 and commercially available reagents and by an operation in thesame manner as in the above-mentioned Examples 47 and 57.

The compounds B-47 and B-48 shown in the following Table 2 were eachsynthesized using M-1 to M-23 and commercially available reagents and byan operation in the same manner as in the above-mentioned Example 48.

The compounds B-49 and B-50 shown in the following Table 2 were eachsynthesized using M-1 to M-23 and commercially available reagents and byan operation in the same manner as in the above-mentioned Example 49.

Compound B-55 shown in the following Table 2 was synthesized using M-1to M-23 and commercially available reagents and by an operation in thesame manner as in the above-mentioned Examples 55 and 56.

The compounds A-69, B-56, and B-57 shown in the following Table 2 wereeach synthesized using M-1 to M-23 and commercially available reagentsand by an operation in the same manner as in the above-mentioned Example57.

Compound B-58 shown in the following Table 2 was synthesized using M-1to M-23 and commercially available reagents and by an operation in thesame manner as in the above-mentioned Example 58.

The compounds B-62, B-65, and B-66 shown in the following Table 2 wereeach synthesized using M-11, M-23, and commercially available reagentsand by an operation in the same manner as in the above-mentioned Example33.

The structural formulas and physical properties of the synthesisintermediate compounds M-1 to M-16 are shown in Table 1-1 and Table 1-2,and the structural formulas and physical properties of M-17 to M-23 areshown in Table 1-3.

TABLE 1-1 Compound No. Structure Analysis data M-1 

1H-NMR (300 MHz, DMSO-d6) δ 7.33-7.25 (2H, m), 6.98 (1H, d, J = 3.6 Hz),2.15 (3H, s), 1.48 (9H, s). MS (ESI) m/z 253 (M + H)+ M-2 

1H-NMR (300 MHz, DMSO-d6) δ 7.11 (1H, s), 6.32 (1H, s), 2.95-2.65 (3H,m), 2.50 (3H, s), 1.35 (9H, s). MS (ESI) m/z 253 (M + H)+ M-3 

1H-NMR (300 MHz, CDCl3) δ 7.70 (1H, d, J = 3.9 Hz), 7.66 (1H, s), 7.63(1H, d, J = 3.9 Hz), 7.16 (1H, d, J = 3.9 Hz), 2.16 (3H, s), 1.51 (9H,s). MS (ESI) m/z 269 (M + H)+ M-4 

1H-NMR (300 MHz, CDCl3) δ 7.72 (1H, d, J = 3.6 Hz), 6.85 (1H, d, J = 3.8Hz), 3.24-2.65 (3H, m), 1.42 (9H, s), 1.19 (3H, d, J = 6.9 Hz). MS (ESI)m/z 271 (M + H)+ M-5 

1H-NMR (300 MHz, CDCl3) δ 3.96 (2H, t, J = 5.4 Hz), 3.80 (2H, s), 3.34(2H, t, J = 5.9 Hz), 2.03 (2H, m), 1.50 (9H, s), 1.17- 1.07 (21H, m).M-6 

MS (ESI) m/z 360 (M + H)+ M-7 

1H-NMR (300 MHz, CDCl3) δ 4.97 (1H, sep, J = 6.0 Hz), 3.78 (2H, t, J =6.9 Hz), 3.29 (2H, t, J = 8.9 Hz), 3.13 (2H, t, J = 8.9 Hz), 2.78 (2H,t, J = 6.9 Hz), 1.74 (2H, m), 1.42 (6H, d, J = 6.0 Hz), 1.05 (21H, m).M-8 

1H-NMR (300 MHz, DMSO-d6) δ 12.40 (1H, br), 9.36 (2H, br), 9.05 (2H,br), 8.42 (1H, d, J = 2.3 Hz), 7.98 (1H, dd, J = 8.9, 2.3 Hz), 7.34 (1H,d, J = 8.9 Hz). MS (ESI) m/z 182 (M + H)+ M-9 

1H-NMR (300 MHz, DMSO-d6) δ 11.58 (1H, br), 9.12 (2H, br), 8.83 (2H,br), 8.04 (1H, d, J = 2.4 Hz), 7.69 (1H, dd, J = 8.7, 2.4 Hz), 7.10 (1H,d, J = 8.7 Hz). MS (ESI) m/z 215 [M(79Br) + H]+, 217 [M(81Br) + H]+ M-10

1H-NMR (300 MHz, DMSO-d6) δ 11.50 (1H, br), 9.12 (2H, br), 8.81 (2H,br), 7.91 (1H, d, J = 2.3 Hz), 7.66 (1H, dd, J = 8.7, 2.3 Hz), 7.13 (1H,d, J = 8.7 Hz). MS (ESI) m/z 171 [M(35Cl) + H]+, 173 [M(37Cl) + H]+ M-11

1H-NMR (300 MHz, DMSO-d6) δ 11.28 (1H, brs), 9.19 (2H, brs), 9.02 (2H,brs), 7.75 (1H, dd, J = 2.4, 12.0 Hz), 7.59 (1H, m), 7.18 (1H, dd, J =8.4, 8.7 Hz). MS (ESI) m/z 155 (M + H)+ M-12

1H-NMR (300 MHz, DMSO-d6) δ 9.38-8.61 (4H, br), 7.50 (1H, dd, J = 9.6,8.4 Hz), 6.78-6.73 (2H, m). MS (ESI) m/z 155 (M + H)+ M-13

1H-NMR (300 MHz, CDCl3) δ 4.20-4.08 (4H, m), 2.92 (1H, dq, J = 30.6, 7.2Hz), 1.48 (9H, s), 1.45 (3H, d, J = 7.2 Hz), 1.40- 1.30 (6H, m). M-14

1H-NMR (300 MHz, CDCl3) δ 4.20-4.09 (4H, m), 2.76 (1H, ddd, J = 22.1,10.4, 4.3 Hz), 2.00-1.83 (2H, m), 1.48 (9H, s), 1.35 (3H, t, J = 7.2Hz), 1.34 (3H, t, J = 7.1 Hz), 0.99 (3H, td, J = 7.5, 1.1 Hz). M-15

1H-NMR (300 MHz, CDCl3) δ 4.20-4.09 (4H, m), 2.85 (1H, ddd, J = 22.3,11.2, 3.8 Hz), 2.05-1.73 (4H, m), 1.47 (9H, s), 1.45-1.29 (6H, m), 0.93(3H, t, J = 7.2 Hz). M-16

1H-NMR (300 MHz, CDCl3) δ 5.08 (1H, sep, J = 6.3 Hz), 4.29- 4.18 (4H,m), 3.57 (1H, dq, J = 19.2, 7.3 Hz), 1.69 (3H, dd, J = 15.6, 7.3 Hz),1.45 (6H, d, J = 6.3 Hz), 1.37 (6H, t, J = 6.9 Hz). M-17

1H-NMR (300 MHz, DMSO-d6) δ 4.08-3.98 (4H, m), 2.85 (1H, ddd, J = 22.8,11.4, 3.3 Hz), 1.85-1.75 (1H, m), 1.60-1.45 (2H, m), 1.50 (9H, s), 1.22(6H, m), 0.88 (6H, d, J = 7.5 Hz). MS (ESI) m/z 309 (M + H)+ M-18

1H-NMR (300 MHz, DMSO-d6) δ 8.26 (3H, br s), 4.23 (1H, m), 3.72 (3H, s),3.00 (1H, dd, J = 14.3, 3.5 Hz), 2.92 (1H, dd, J = 14.3, 8.0 Hz). MS(ESI) m/z 184 (M + H)+ M-19

1H-NMR (300 MHz, DMSO-d6) δ 8.50 (3H, br s), 4.12 (4H, m), 3.30 (2H, d,J = 13.5 Hz), 1.28 (6H, t, J = 7.1 Hz). MS (ESI) m/z 168 (M + H)+ M-20

1H-NMR (400 MHz, CDCl3) δ 3.75 (2H, s), 3.29 (2H, t, J = 6.4 Hz), 2.94(2H, d, J = 6.4 Hz), 1.51 (9H, s), 1.47 (9H, s). MS (ESI) m/z 246 (M +H)+ M-21

1H-NMR (400 MHz, DMSO-d6) δ 5.87 (1H, ddt, J = 17.1, 10.2, 6.1 Hz), 5.19(1H, ddt, J = 17.1, 3.2, 1.7 Hz), 5.11 (1H, ddt, J = 10.2, 3.2, 1.2 Hz),3.29 (2H, s), 3.25 (2H, ddd, J = 6.1, 1.7, 1.2 Hz), 1.47 (9H, s). MS(ESI) m/z 172 (M + H)+ M-22

1H-NMR (400 MHz, CDCl3) δ 7.23 (1H, d, J = 3.6 Hz), 6.22 (1H, d, J = 3.6Hz), 3.01 (2H, t, J = 7.6 Hz), 2.63 (2H, t, J = 7.6 Hz), 1.44 (9H, s).MS (ESI) m/z 241 (M + H)+ M-23

1H-NMR (300 MHz, DMSO-d6) δ 7.54 (1H, d, J = 3.3 Hz), 6.94 (1H, d, J =3.3 Hz), 3.04 (2H, t, J = 7.5 Hz), 2.59 (2H, t, J = 7.5 Hz), 1.38 (9H,s). MS (ESI) m/z 257 (M+H)+

The structural formulas and physical properties of compounds A-1 toA-40, B-1 to B-24, and C-1 to C-3 are shown in Table 2-1 to Table 2-10,and the structural formulas and physical properties of A-41 to A-74,B-25 to B-66, C-4, and C-5 are shown in Table 2-11 to Table 2-22.

TABLE 2-1 Compound No. Structure Analysis data A-1 

1H-NMR (DMSO-d6) δ 9.34 (br s, 2H), 6.95 (br s, 2H), 8.12 (d, J = 7.8Hz, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 3.9 Hz, 1H), 7.60 (d, J= 8.7 Hz, 2H), 7.21 (s, 1H), 7.05 (d, J = 3.9 Hz, 1H), 4.37 (m, 1H),3.76 (m, 2H), 2.73 (s, 1H), 2.24 (s, 3H). MS (ESI) m/z 402 (M + H)+ A-2 

1H-NMR (DMSO-d6) δ 9.34 (br s, 2H), 8.95 (br s, 2H), 8.48 (m, 1H), 7.91(d, J = 8.7 Hz, 2H), 7.72 (d, J = 3.9 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H),7.21 (s, 1H), 7.05 (d, J = 3.9 Hz, 1H), 3.84 (m, 2H), 2.73 (s, 1H), 2.24(s, 3H). MS (ESI) m/z 372 (M + H)+ A-3 

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 8.95 (2H, br s), 7.91 (2H,d, J = 8.7 Hz), 7.72 (1H, d, J = 3.9 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.43(1H, s), 7.14 (1H, d, J = 3.9 Hz), 2.73 (1H, s), 2.24 (3H, s). MS (ESI)m/z 315 (M + H)+ A-4 

MS (ESI) m/z 374 (M + H)+ A-5 

MS (ESI) m/z 404 (M + H)+ A-6 

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.10 (2H, br s), 7.90 (2H,d, J = 6.9 Hz), 7.61-7.52 (3H, m), 6.52 (1H, d, J = 3.6 Hz), 3.13-2.98(1H, m), 2.91-2.70 (2H, m), 1.14 (3H, d, J = 6.9 Hz). MS (ESl) m/z 317(M + H)+ A-7 

MS (ESI) m/z 430 (M + H)+ A-8 

1H-NMR (300 MHz, DMSO-d6) δ 9.65-9.28 (4H, m), 8.63 (1H, d, J = 2.3 Hz),8.24 (1H, dd, J = 8.6, 2.3 Hz), 7.97 (1H, d, J = 8.6 Hz), 7.91 (1H, d, J= 3.5 Hz), 7.43 (1H, s), 7.18 (1H, d, J = 3.5 Hz), 2.22 (3H, s). MS(ESI) m/z 360 (M + H)+ A-9 

MS (ESI) m/z 432 (M + H)+ A-10

MS (ESI) m/z 448 (M + H)+ A-11

MS (ESI) m/z 386 (M + H)+ A-12

MS (ESI) m/z 444 (M + H)+ A-13

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.02 (2H, br s), 8.35 (1H,d, J = 7.5 Hz), 7.91 (2H, d, J = 8.7 Hz), 7.72 (1H, d, J = 3.3 Hz), 7.59(2H, d, J = 7.5 Hz), 7.18 (1H, s), 7.04 (1H, d, J = 3.3 Hz), 4.35-4.22(2H, m), 2.42- 2.30 (2H, m), 2.22 (3H, s), 2.15-1.81 (2H, m). MS (ESI)m/z 444 (M + H)+ A-14

MS (ESI) m/z 416 (M + H)+ A-15

MS (ESI) m/z 446 (M + H)+ A-16

MS (ESI) m/z 418 (M + H)+ A-17

MS (ESI) m/z 388 (M + H)+ A-18

1H-NMR (DMSO-d6) δ 9.35 (br s, 2H), 9.12 (br s, 2H), 8.41-8.27 (m, 1H),7.90 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.54-7.49 (m, 1H),6.57-6.42 (m, 1H), 4.62- 4.40 (m, 1H), 3.13-2.42 (m, 5H), 1.17-0.99 (m,3H). MS (ESI) m/z 432 (M + H)+ A-19

MS (ESI) m/z 414 (M + H)+ A-20

MS (ESI) m/z 430 (M + H)+ A-21

MS (ESI) m/z 430 (M + H)+ A-22

1H-NMR (300 MHz, DMSO-d6) δ 12.53 (1H, br s), 9.34 (2H, s), 8.98 (2H, brs), 8.25 (1H, d, J = 7.9 Hz), 7.89 (2H, d, J = 8.7 Hz), 7.55 (2H, d, J =8.7 Hz), 7.51 (1H, d, J = 3.5 Hz), 7.34 (1H, s), 6.90 (1H, s), 6.51 (1H,d, J = 3.5 Hz), 4.49 (1H, m), 2.99 (1H, dd, J = 14.4, 6.4 Hz), 2.81-2.41(4H, m), 1.05 (3H, d, J = 5.6 Hz). MS (ESI) m/z 431 (M + H)+ A-23

1H-NMR (300 MHz, DMSO-d6) δ 9.33 (2H, br s), 9.05 (2H, br s), 8.20 (1H,d, J = 7.6 Hz), 7.89 (2H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.51(1H, d, J = 3.5 Hz), 7.35 (1H, s), 6.88 (1H, s), 6.48 (1H, d, J = 3.5Hz), 4.49 (1H, m), 2.97 (1H, dd, J = 13.7, 6.0 Hz), 2.83-2.38 (4H, m),1.07 (3H, d, J = 6.2 Hz). MS (ESI) m/z 431 (M + H)+ A-24

1H-NMR (300 MHz, DMSO-d6) δ 12.56 (1H, br s), 9.34 (2H, br s), 8.98 (2H,br s), 8.28 (1H, d, J = 7.6 Hz), 7.89 (2H, d, J = 8.7 Hz), 7.55 (2H, d,J = 8.7 Hz), 7.52 (1H, d, J = 3.5 Hz), 7.29 (1H, s), 6.78 (1H, s), 6.51(1H, d, J = 3.5 Hz), 4.15 (1H, m), 2.99 (1H, dd, J = 14.1, 6.5 Hz),2.82-2.70 (2H, m), 2.15-2.10 (2H, m), 1.98-1.76 (2H, m), 1.08 (3H, d, J= 6.5 Hz). MS (ESI) m/z 445 (M + H)+ A-25

1H-NMR (300 MHz, DMSO-d6) δ 12.56 (1H, br s), 9.34 (2H, br s), 9.00 (2H,br s), 8.26 (1H, d, J = 7.9 Hz), 7.89 (2H, d, J = 8.7 Hz), 7.55 (2H, d,J = 8.7 Hz), 7.52 (1H, d, J = 3.5 Hz), 7.25 (1H, s), 6.77 (1H, s), 6.48(1H, d, J = 3.5 Hz), 4.15 (1H, m), 2.99 (1H, dd, J = 13.2, 6.2 Hz),2.82-2.72 (2H, m), 2.10-2.04 (2H, m), 1.93-1.74 (2H, m), 1.07 (3H, d, J= 6.4 Hz). MS (ESI) m/z 445 (M + H)+ A-26

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br), 9.02 (2H, br), 7.89 (2H, d, J= 8.9 Hz), 7.55 (2H, d, J = 8.9 Hz), 7.51 (1H, d, J = 3.5 Hz), 6.50 (1H,d, J = 3.5 Hz), 4.17 (2H, s), 3.94 (2H, s), 3.10-2.95 (2H, m), 2.76 (1H,dd, J = 14.9, 5.9 Hz), 1.06 (3H, d, J = 6.5 Hz). MS (ESI) m/z 432 (M +H)+ A-27

1H-NMR (DMSO-d6) δ 9.34 (br s, 2H), 9.05 (br s, 2H), 8.33-8.18 (m, 1H),7.90 (d, J = 8.7 Hz, 2H), 7.61-7.42 (m, 3H), 6.57-6.42 (m, 1H),4.27-4.16 (m, 1H), 3.09-2.90 (m, 1H), 2.90-2.63 (m, 2H), 2.37-2.08 (m,2H), 2.05-1.87 (m, 1H), 1.86-1.63 (m, 1H), 1.08 (d, J = 5.7 Hz, 3H). MS(ESI) m/z 446 (M + H)+ A-28

1H-NMR (DMSO-d6) δ 9.35 (br s, 2H), 9.12 (br s, 2H), 8.41-8.27 (m, 1H),7.90 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.54-7.49 (m, 1H),6.57-6.42 (m, 1H), 4.62- 4.40 (m, 1H), 3.13-2.42 (m, 5H), 1.17-0.99 (m,3H). MS (ESI) m/z 432 (M + H)+ A-29

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.13 (2H, br s), 7.90 (2H,d, J = 8.7 Hz), 7.63-7.49 (3H, m), 6.51 (1H, d, J = 3.6 Hz), 3.10-2.82(2H, m), 2.69-2.55 (1H, m), 1.64-1.49 (2H, m), 0.90 (3H, t, J = 7.5 Hz).MS (ESI) m/z 331 (M + H)+ A-30

MS (ESI) m/z 460 (M + H)+ A-31

1H-NMR (DMSO-d6) δ 9.34 (br s, 2H), 9.05 (br s, 2H), 8.43-8.29 (m, 1H),7.89 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.52-7.46 (m, 1H),6.53-6.42 (m, 1H), 4.60- 4.44 (m, 1H), 3.07-2.51 (m, 5H), 1.61-1.38 (m,2H), 0.97- 0.77 (m, 3H). MS (ESI) m/z 446 (M + H)+ A-32

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.01 (2H, s), 7.89 (2H, d, J =8.7 Hz), 6.64 (1H, d, J = 3.6 Hz), 7.57 (3H, m), 3.89 (2H, s). MS (ESl)m/z 289 (M + H)+ A-33

1H-NMR (DMSO-d6) δ 9.42 (br s, 2H), 9.16 (br s, 2H), 7.93 (d, J = 9.9Hz, 1H), 7.78-7.70 (m, 2H), 7.62 (d, J = 3.3 Hz, 1H), 6.55 (d, J = 3.3Hz, 1H), 3.13-2.99 (m, 1H), 2.92-2.73 (m, 2H), 1.14 (d, J = 6.9 Hz, 3H).MS (ESI) m/z 335 (M + H)+ A-34

MS (ESI) m/z 345 (M + H)+ A-35

1H-NMR (DMSO-d6) δ 9.42 (br s, 2H), 9.19 (br s, 2H), 8.42-8.31 (m, 1H),7.93 (d, J = 11.4 Hz, 1H), 7.81-7.69 (m, 2H), 7.61-7.56 (m, 1H),6.56-6.45 (m, 1H), 4.61-4.42 (m, 1H), 3.11-2.88 (m, 2H), 2.87-2.47 (m,3H), 1.06 (t, J = 6.6 Hz, 1H). MS (ESI) m/z 450 (M + H)+ A-36

1H-NMR (300 MHz, DMSO-d6) δ 9.32 (2H, br), 8.90 (2H, br), 7.87 (2H, d, J= 8.7 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.51 (1H, d, J = 3.6 Hz), 6.54 (1H,d, J = 3.6 Hz), 2.73-2.57 (3H, m), 1.05 (3H, d, J = 6.9 Hz). MS (ESI)m/z 353 (M + H)+ A-37

1H-NMR (300 MHz, DMSO-d6) δ 9.33 (2H, s), 9.01 (2H, s), 7.89 (2H, d, J =8.4 Hz), 7.54 (3H, m), 6.52 (1H, d, J = 3.6 Hz), 2.98 (2H, t, J = 7.2Hz), 2.66 (2H, t, J = 7.2 Hz). MS (ESI) m/z 303 (M + H)+ A-38

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.02 (2H, s), 8.36 (1H, d, J =8.1 Hz), 7.89 (2H, d, J = 8.7 Hz), 7.53 (3H, m), 6.48 (1H, d, J = 3.3Hz), 4.54 (1H, m), 2.97 (2H, t, J = 7.2 Hz), 2.50-2.73 (4H, m). MS (ESI)m/z 418 (M + H)+ A-39

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.09 (2H, s), 8.55 (1H, d, J =7.8 Hz), 7.89 (2H, d, J = 8.7 Hz), 7.56 (3H, m), 6.58 (1H, d, J = 3.6Hz), 4.53 (1H, m), 2.89 (2H, s), 2.64 (2H, m). MS (ESI) m/z 404 (M + H)+A-40

MS (ESI) m/z 360 (M + H)+ B-1 

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, s), 9.00 (2H, s), 8.09 (1H, d, J =3.9 Hz), 7.88 (3H, m), 7.60 (3H, m), 2.18 (3H, s). MS (ESI) m/z 331 (M +H)+ B-2 

1H-NMR (300 MHz, DMSO-d6) δ 9.30 (2H, brs), 9.10 (2H, brs), 8.50 (1H, t,J = 5.7 Hz), 8.06 (1H, d, J = 3.0 Hz), 7.89 (2H, d, J = 8.1 Hz), 7.58(2H, d, J = 8.1 Hz), 7.54 (1H, s), 7.50 (1H, d, J = 3.0 Hz), 3.82 (2H,d, J = 5.7 Hz), 2.18 (3H, s). MS (ESI) m/z 388 (M + H)+ B-3 

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, s), 8.99 (2H, s), 8.61 (1H, m),8.06 (1H, d, J = 3.6 Hz), 7.89 (2H, d, J = 8.4 Hz), 7.59 (2H, d, J = 8.4Hz), 7.54 (1H, s), 7.50 (1H, d, J = 3.9 Hz), 4.36 (1H, m), 3.74 (2H, d,J = 4.8 Hz), 2.19 (3H, s). MS (ESI) m/z 418 (M + H)+ B-4 

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, s), 8.99 (2H, s), 8.04 (1H, m),7.90 (2H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.43 (1H, m), 6.84(1H, m), 4.01 (2H, t), 3.20-3.50 (4H, m), 2.17 (3H, s), 1.70 (2H, m). MS(ESI) m/z 446 (M + H)+ B-5 

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 8.99 (2H, s), 7.90 (3H, m),7.56 (2H, d, J = 9.0 Hz), 7.07 (1H, m), 4.01 (1H, d, J = 11.7 Hz), 3.80(1H, d, J = 17.1 Hz), 3.42 (2H, m), 3.15 (3H, m), 2.90 (2H, m), 1.55(2H, m), 1.10 (3H, d, J = 4.8 Hz). MS (ESI) m/z 448 (M + H)+ B-6 

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.01 (2H, s), 7.91 (2H, m),7.56 (1H, d, J = 9.0 Hz), 7.10 (1H, d, J = 3.6 Hz), 3.37 (1H, m), 3.01(1H, m), 2.73 (1H, m), 1.13 (3H, d, J = 4.2 Hz). MS (ESI) m/z 333 (M +H)+ B-7 

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, s), 8.91 (2H, s), 8.03 (1H, d, J =4.2 Hz), 7.90 (2H, d, J = 8.7 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.40 (1H,d, J = 4.2 Hz), 6.84 (1H, s), 4.48 (1H, brs), 3.55 (2H, m), 3.20-3.45(4H, m), 2.70 (2H, m), 2.15 (3H, s), 1.67 (2H, m). MS (ESI) m/z 496 (M +H)+ B-8 

1H-NMR (300 MHz, DMSO-d6) δ 9.56 (2H, br), 9.26 (2H, br), 8.65 (1H, d, J= 2.4 Hz), 8.27 (1H, dd, J = 8.6, 2.4 Hz), 8.15 (1H, d, J = 5.2 Hz),7.98 (1H, d, J = 8.6 Hz), 7.90 (1H, s), 7.69 (1H, d, J = 5.2 Hz), 2.19(3H, s). MS (ESI) m/z 376 (M + H)+ B-9 

MS (ESI) m/z 378 (M + H)+ B-10

MS (ESI) m/z 491 (M + H)+ B-11

1H-NMR (300 MHz, DMSO-d6) δ 9.62 (2H, br), 9.30 (2H, br), 8.64 (1H, d, J= 2.1 Hz), 8.26 (1H, dd, J = 8.4, 2.1 Hz), 7.94-7.91 (2H, m), 7.14-7.11(1H, m), 4.57-3.77 (3H, m), 3.51-2.92 (6H, m), 1.62-1.51 (2H, m),1.12-1.04 (3H, m). MS (ESI) m/z 493 (M + H)+ B-12

MS (ESI) m/z 390 (M + H)+ B-13

1H-NMR (300 MHz, DMSO-d6) δ 9.57 (2H, s), 9.17 (2H, s), 8.64 (1H, s),8.25 (1H, dd, J = 2.4, 8.7 Hz), 8.09 (1H, d, J = 4.2 Hz), 7.98 (1H, d, J= 8.7 Hz), 7.43 (1H, d, J = 4.2 Hz), 6.86 (1H, s), 3.60-3.25 (6H, m),2.71 (2H, m), 2.15 (3H, s), 1.68 (2H, m). MS (ESI) m/z 540 (M + H)+ B-14

MS (ESI) m/z 465 (M + H)+ B-15

MS (ESI) m/z 465 (M + H)+ B-16

MS (ESI) m/z 411 [M(79Br) + H]+, 413 [M(81Br) + H]+ B-17

1H-NMR (300 MHz, DMSO-d6) δ 12.42 (1H, br), 9.43 (2H, s), 9.24 (2H,brs), 8.11 (1H, d, J = 2.2 Hz), 7.96 (1H, d, J = 3.7 Hz), 7.86 (1H, dd,J = 8.7, 2.2 Hz), 7.78 (1H, d, J = 8.7 Hz), 7.13 (1H, d, J = 3.7 Hz),3.19 (1H, dd, J = 14.8, 8.0 Hz), 3.04 (1H, dd, J = 14.8, 6.0 Hz), 2.75(1H, m), 1.14 (3H, d, J = 7.2 Hz). MS (ESI) m/z 367 [M(35Cl) + H]+, 368[M(37Cl) + H]+ B-18

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 8.99 (2H, s), 8.29 (1H, m),7.90 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.05 (1H, m), 4.50(1H, m), 3.20-2.50 (5H, s), 1.06 (3H, m). MS (ESI) m/z 448 (M + H)+ B-19

1H-NMR (300 MHz, DMSO-d6) δ 12.41 (1H, brs), 9.41 (2H, s), 9.15 (2H,brs), 7.97-7.75 (4H, m), 7.13 (1H, d, J = 3.9 Hz), 3.19 (1H, dd, J =15.0, 8.4 Hz), 3.04 (1H, dd, J = 15.0, 6.0 Hz), 2.75 (1H, m), 1.14 (3H,d, J = 7.2 Hz). MS (ESI) m/z 351 (M + H)+ B-20

1H-NMR (300 MHz, DMSO-d6) δ 9.41 (2H, br), 9.12 (2H, br), 8.33-8.27 (1H,m), 7.95-7.92 (2H, m), 7.76-7.74 (2H, m), 7.10-7.07 (1H, m), 4.54-4.48(1H, m), 3.46-2.50 (5H, m), 1.10-1.04 (3H, m). MS (ESI) m/z 466 (M + H)+B-21

1H-NMR (300 MHz, DMSO-d6) δ 12.24 (1H, br), 9.41 (2H, br), 9.13 (2H,br), 8.23-8.17 (1H, m), 7.94-7.91 (2H, m), 7.76-7.74 (2H, m), 7.10-7.07(1H, m), 4.24-4.17 (1H, m), 3.47-1.71 (7H, m), 1.10-1.07 (3H, m). MS(ESI) m/z 480 (M + H)+ B-22

1H-NMR (300 MHz, DMSO-d6) δ 9.41 (2H, br), 9.12 (2H, br), 8.33-8.27 (1H,m), 7.95-7.92 (2H, m), 7.76-7.74 (2H, m), 7.10-7.07 (1H, m), 4.54-4.48(1H, m), 3.46-2.50 (5H, m), 1.10-1.04 (3H, m). MS (ESI) m/z 466 (M + H)+B-23

1H-NMR (300 MHz, DMSO-d6) δ 9.36 (2H, br), 9.02 (2H, br), 8.31-8.19 (1H,m), 7.91-7.87 (3H, m), 7.55 (2H, d, J = 8.5 Hz), 7.08-7.04 (1H, m),4.52-4.42 (1H, m), 3.51- 2.54 (5H, m), 1.09-1.04 (3H, m). MS (ESI) m/z448 (M + H)+ B-24

1H-NMR (300 MHz, DMSO-d6) δ 12.40 (1H, br), 9.49 (2H, br), 9.24 (2H,br), 7.91 (1H, d, J = 3.8 Hz), 7.80 (1H, dd, J = 8.5, 8.2 Hz), 7.63 (1H,dd, J = 10.9, 2.0 Hz), 7.41 (1H, dd, J = 8.5, 2.0 Hz), 7.11 (1H, dd, J =3.8 Hz), 3.18 (1H, dd, J = 15.0, 7.6 Hz), 3.03 (1H, dd, J = 15.0, 6.2Hz), 2.77-2.70 (1H, m), 1.13 (3H, d, J = 7.0 Hz). MS (ESI) m/z 351 (M +H)+ C-1 

1H-NMR (DMSO-d6) δ 9.36 (2H, br s), 9.09 (2H, br s), 7.93 (2H, d, J =8.6 Hz), 7.75 (1H, s), 7.63 (2H, d, J = 8.6 Hz), 2.33 (3H, s), 2.30 (1H,s). MS (ESI) m/z 332 (M + H)+ C-2 

MS (ESI) m/z 447 (M + H)+ C-3 

MS (ESI) m/z 419 (M + H)+ A-41

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.08 (2H, br s), 7.90 (2H,dd, J = 6.9, 1.8 Hz), 7.61-7.49 (3H, m), 6.52 (1H, d, J = 3.6 Hz),3.15-2.98 (1H, m), 2.90-2.70 (2H, m), 1.14 (3H, d, J = 6.9 Hz). MS (ESI)m/z 317 (M + H)+ A-42

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.08 (2H, br s), 7.90 (2H,dd, J = 6.9, 1.8 Hz), 7.61-7.49 (3H, m), 6.52 (1H, d, J = 3.6 Hz),3.15-2.98 (1H, m), 2.90-2.70 (2H, m), 1.14 (3H, d, J = 6.9 Hz). MS (ESI)m/z 317 (M + H)+ A-43

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.10 (2H, br s), 8.32 (1H,d, J = 8.7 Hz), 7.90 (2H, d, J = 8.7 Hz), 7.54 (2H, d, J = 8.7 Hz), 7.50(1H, d, J = 3.3 Hz), 6.46 (1H, d, J = 3.3 Hz), 4.59-4.49 (1H, m),3.08-2.47 (5H, m), 1.07 (3H, d, J = 5.4 Hz). MS (ESI) m/z 432 (M + H)+A-44

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.09 (2H, br s), 8.36 (1H,d, J = 8.4 Hz), 7.90 (2H, d, J = 8.7 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.51(1H, d, J = 3.6 Hz), 6.50 (1H, d, J = 3.6 Hz), 4.57-4.45 (1H, m),3.05-2.42 (5H, m), 1.05 (3H, d, J = 6.6 Hz). MS (ESI) m/z 432 (M + H)+A-45

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.09 (2H, br s), 8.36 (1H,d, J = 8.4 Hz), 7.90 ( 2H, d, J = 8.7 Hz), 7.55 (2H, d, J = 8.7 Hz),7.51 (1H, d, J = 3.6 Hz), 6.50 (1H, d, J = 3.6 Hz), 4.57-4.45 (1H, m),3.05-2.42 (5H, m), 1.05 (3H, d, J = 6.6 Hz). MS (ESI) m/z 432 (M + H)+A-46

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.10 (2H, br s), 8.32 (1H,d, J = 8.7 Hz), 7.90 ( 2H, d, J = 8.7 Hz), 7.54 (2H, d, J = 8.7 Hz),7.50 (1H, d, J = 3.3 Hz), 6.46 (1H, d, J = 3.3 Hz), 4.59-4.49 (1H, m),3.08-2.47 (5H, m), 1.07 (3H, d, J = 5.4 Hz). MS (ESI) m/z 432 (M + H)+A-47

1H-NMR (300 MHz, DMSO-d6) δ 9.32 (2H, s), 9.00 (2H, s), 8.00 (1H, t, J =5.4 Hz), 7.87 (2H, d, J = 8.7 Hz), 7.52 (2H, m), 7.30-7.10 (6H, m), 6.40(1H, d, J = 3.3 Hz), 3.30-3.20 (2H, m), 3.00-2.90 (1H, m), 2.70-2.60(4H, m), 1.01 (3H, d, J = 6.6 Hz). MS (ESl) m/z 420 (M + H)+ A-48

1H-NMR (300 MHz, DMSO-d6) δ 9.20-9.05 (4H, br s), 7.92-7.82 (3H, m),7.52 (3H, m), 6.45 (1H, d, J = 3.6 Hz), 3.30- 3.20 (2H, m), 3.10-2.90(1H, m), 2.75-2.65 (2H, m), 1.47 (1H, m), 1.24 (2H, m), 1.05 (3H, d, J =6.6 Hz), 0.83 (6H, d, J = 6.6 Hz). MS (ESl) m/z 386 (M + H)+ A-49

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, s), 9.19 (2H, s), 8.27 (1H, t, J =5.4 Hz), 7.91 (2H, d, J = 9.0 Hz), 7.54 (3H, m), 6.50 (1H, d, J = 3.6Hz), 3.18-2.98 (5H, m), 2.85-2.65 (8H, m), 1.08 (3H, d, J = 6.6 Hz). MS(ESI) m/z 387 (M + H)+ A-50

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.02 (2H, s), 7.95 (1H, t, J =5.4 Hz), 7.89 (2H, d, J = 8.7 Hz), 7.54 (3H, m), 6.47 (1H, d, J = 3.6Hz), 3.30 (2H, m), 3.10 (2H, m), 2.98 (1H, m), 2.78-2.68 (2H, m), 1.06(3H, d, J = 6.3 Hz). MS (ESI) m/z 360 (M + H)+ A-51

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 8.93 (2H, s), 7.89 (2H, d, J =9.0 Hz), 7.54 (3H, m), 6.47 (1H, d, J = 3.6 Hz), 3.60-3.00 (5H, m), 2.72(2H, m), 1.90-1.70 (4H, m), 1.07 (3H, d, J = 5.7 Hz). MS (ESl) m/z 370(M + H)+ A-52

1H-NMR (400 MHz, DMSO-d6) δ 9.34 (2H, s), 8.98 (2H, s), 7.89 (2H, m),7.55 (3H, m), 6.48 (1H, d, J = 3.2 Hz), 3.90- 3.80 (2H, m), 3.55-3.25(2H, m), 3.08-2.98 (2H, m), 2.80- 2.70 (2H, m), 2.10-1.20 (4H, m), 1.07(3H, d, J = 6.4 Hz), MS (ESl) m/z 428 (M + H)+ A-53

1H-NMR (400 MHz, DMSO-d6) δ 9.35 (2H, s), 9.01 (2H, s), 8.37 (1H, d, J =8.0 Hz), 7.57 (1H, d, J = 2.0 Hz), 7.52-7.44 (3H, m), 6.47 (1H, d, J =2.0 Hz), 4.55 (1H, m), 3.88 (3H, s), 2.97 (2H, t, J = 7.6 Hz), 2.68-2.55(4H, m). MS (ESl) m/z 448 (M + H)+ A-54

1H-NMR (400 MHz, DMSO-d6) δ 9.34 (2H, s), 8.96 (2H, s), 7.89 (2H, dd, J= 6.8, 2.0 Hz), 7.54 (3H, m), 6.52 (0.5H, d, J = 3.6 Hz), 6.48 (0.6H, d,J = 3.6 Hz), 4.23 (1H, s), 3.96 (1H, s), 3.60 (1H, t, J = 8.8 Hz), 3.46(1H, t, J = 6.8 Hz), 2.98-2.85 (2H, m), 2.70-2.40 (2H, m). MS (ESI) m/z418 (M + H)+ A-55

1H-NMR (400 MHz, DMSO-d6) δ 9.35 (1H, br s), 9.26- 9.02 (2H, m),7.95-7.86 (2H, m), 7.58-7.51 (2H, m), 6.52- 6.47 (3H, m), 5.94-5.62 (1H,m), 5.23-5.03 (2H, m), 4.13- 3.88 (4H, m), 3.04-2.91 (2H, m), 2.83-2.65(2H, m). MS (ESI) m/z 400 (M + H)+ A-56

MS (ESI) m/z 410 (M + H)+ A-57

1H-NMR (300 MHz, DMSO-d6) δ 8.89 (2H, br), 8.89 (1H, br), 8.26-8.21 (1H,m), 7.89 (2H, d, J = 8.5 Hz), 7.59-7.56 (2H, m), 7.51-7.49 (1H, m),6.57-6.55 (1H, m), 4.38-4.34 (1H, m), 3.12-2.72 (5H, m), 1.08 (3H, d, J= 6.5 Hz). MS (ESI) m/z 468 (M + H)+ A-58

1H-NMR (300 MHz, DMSO-d6) δ 9.23 (4H, br s), 7.88 (2H, d, J = 8.7 Hz),7.55 (1H, d, J = 3.4 Hz), 7.54 (2H, d, J = 8.7 Hz), 6.52 (1H, d, J = 3.4Hz), 1.73-2.37 (7H, m), 0.89 (3H, d, J = 6.7 Hz). MS (ESI) m/z 345 (M +H)+ A-59

1H-NMR (300 MHz, DMSO-d6) δ 9.33 (2H, br s), 9.10 (2H, br s), 8.10 (1H,d, J = 7.6 Hz), 7.89 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.55(1H, d, J = 3.5 Hz), 6.53-6.51 (1H, m), 4.50- 4.43 (1H, m), 2.75 (1H,dd, J = 15.0, 6.2 Hz), 2.69-2.47 (3H, m), 2.25-2.11 (2H, m), 1.88-1.81(1H, m), 1.63-1.57 (1H, m), 1.41-1.34 (1H, m), 0.89 (3H, d, J = 6.6 Hz).MS (ESI) m/z 460 (M + H)+ A-60

1H-NMR (300 MHz, DMSO-d6) δ 9.31 (2H, br s), 9.26 (2H, br s), 7.90 (2H,d, J = 8.7 Hz), 7.55 (3H, m), 6.51 (1H, d, J = 3.6 Hz), 3.00 (1H, m),2.90 (1H, m), 2.73 (1H, m), 2.28 (2H, m), 1.77 (2H m). MS (ESI) m/z 375(M + H)+ A-61

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.06 (2H, s), 8.40 (1H, m),8.89 (2H, d, J = 8.7 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.50 (1H, d, J = 3.3Hz), 6.48 (1H, m), 4.50 (1H, m), 2.95- 2.40 (5H, m), 2.22 (2H, m),1.80-1.60 (2H, m). MS (ESI) m/z 490 (M + H)+ A-62

1H-NMR (300 MHz, DMSO-d6) δ 9.33 (2H, s), 9.05 (2H, s), 8.51 (1H, s),8.24 (0.5H, d, J = 7.8 Hz), 8.26 (0.5H, d, J = 7.8 Hz), 7.89 (2H, d, J =8.7 Hz), 7.52 (2H, d, J = 8.7 Hz), 6.61 (0.5H, s), 6.58 (0.5H, s), 4.54(1H, m), 3.10-2.80 (5H, m), 1.02 (3H, m). MS (ESI) m/z 432 (M + H)+ A-63

1H-NMR (400 MHz, DMSO-d6) δ 12.35 (1H, br s), 9.41 (2H, br s), 9.18 (2H,br s), 8.62 (1H, d, J = 0.8 Hz), 7.92 (1H, dd, J = 11.6, 1.6 Hz),7.76-7.70 (2H, m), 6.63 (1H, d, J = 0.8 Hz), 2.99 (1H, dd, J = 15.0, 6.6Hz), 2.83-2.72 (2H, m), 1.11 (3H, d, J = 6.8 Hz). MS (ESI) m/z 335 (M +H) A-64

1H-NMR (400 MHz, DMSO-d6) δ 9.33 (2H, s), 8.94 (2H, s), 8.52 (1H, s),8.09 (1H, t, J = 6.8 Hz), 7.89 (2H, d, J = 6.8 Hz), 7.52 (2H, d, J = 6.8Hz), 6.59 (1H, s), 2.92 (1H, dd, J = 14.8, 6.8 Hz), 2.79 (2H, m), 2.67(2H, m), 1.03 (3H, d, J = 6.8 Hz). MS (ESI) m/z 410 (M + H)+ A-65

1H-NMR (400 MHz, DMSO-d6) δ 9.33 (2H, s), 8.91 (2H, s), 8.50 (1H, t),8.19 (1H, t, J = 7.2 Hz), 7.88 (2H, d, J = 6.4 Hz), 7.55 (2H, m), 6.65(0.5H, s), 6.62 (0.5H, s), 4.35 (1H, m), 2.91 (1H, m), 2.80 (2H, m),2.65 (2H, m), 1.05 (3H, d, J = 6.8 Hz). MS (ESI) m/z 468 (M + H)+ A-66

1H-NMR (400 MHz, DMSO-d6) δ 9.40 (2H, br s), 9.07 (2H br s), 8.61 (1H,d, J = 0.8 Hz), 8.29 (1H, m), 7.92 (1H, dd, J = 11.6, 2.0 Hz), 7.75-7.69(2H, m), 6.59 (1H, m), 4.52 (1H, m), 2.90 (1H, m), 2.75-2.55 (4H, m),1.02 (3H, m), MS (ESI) m/z 450 (M + H)+ A-67

1H-NMR (300 MHz, DMSO-d6) δ 9.33 (2H, s), 8.97 (2H, s), 8.23 (1H, m),7.90-7.80 (3H, m), 7.55 (2H, d, J = 8.4 Hz), 7.47 (1H, s), 4.48 (1H, m),3.10-2.90 (3H, m), 2.70-2.50 (2H, m), 1.02 (3H, m). MS (ESI) m/z 432(M + H)+ A-68

1H-NMR (400 MHz, DMSO-d6) δ 9.36 (2H, br s), 8.98 (2H, br s), 8.88 (1H,d, J = 8.0 Hz), 8.01 (4H, s), 7.93 (2H, d, J = 8.8 Hz), 7.79 (1H, d, J =3.6 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.48 (1H, d, J = 3.6 Hz), 4.80-4.75(1H, m), 2.87 (1H, dd, J = 16.0, 5.6 Hz), 2.73 (1H, dd, J = 16.0, 8.0Hz). MS (ESI) m/z 466 (M + H)+ A-69

1H-NMR (400 MHz, DMSO-d6) δ 12.62 (1H, br s), 9.36 (2H, br s), 9.00 (2H,br s), 8.97 (1H, t, J = 6.0 Hz), 8.04- 8.01 (4H, m), 7.92 (2H, d, J =8.8 Hz), 7.78 (1H, d, J = 3.6 Hz), 7.76 (2H, d, J = 8.8 Hz), 7.47 (1H,d, J = 3.6 Hz), 3.95 (2H, d, J = 8.0 Hz). MS (ESI) m/z 408 (M + H)+ A-70

1H-NMR (400 MHz, DMSO-d6) δ 9.31 (2H, br s), 9.20 (2H, br s), 8.66 (1H,t, J = 5.6 Hz), 8.03 (2H, d, J = 8.4 Hz), 7.96 (2H, d, J = 8.4 Hz), 7.90(2H, d, J = 8.8 Hz), 7.77 (1H, d, J = 4.0 Hz), 7.60 (2H, d, J = 8.8 Hz),7.45 (1H, d, J = 4.0 Hz), 3.56 (2H, dd, J = 12.2, 5.6 Hz). MS (ESI) m/z444 (M + H)+ A-71

MS (ESI) m/z 466 (M + H)+ A-72

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, br s), 9.01 (2H, br s), 7.89 (2H,d, J = 8.7 Hz), 7.56 (2H, d, J = 8.7 Hz), 7.54 (1H, s), 6.61-6.49 (1H,m), 5.28-2.19 (1H, m), 3.39-2.60 (5H, m), 1.24-1.04 (3H, m). MS (ESI)m/z 433 (M + H)+ A-73

1H-NMR (400 MHz, DMSO-d6) δ 9.34 (2H, s), 9.15 (2H, s), 7.93-7.87 (2H,m), 7.59-7.51 (3H, m), 6.54 (1H, d, J = 3.6 Hz), 4.37-4.28 (1H, m),3.21-3.03 (2H, m), 3.01-2.62 (3H, m), 1.25-1.13 (3H, m). MS (ESI) m/z449 (M + H)+ A-74

1H-NMR (400 MHz, DMSO-d6) δ 12.50 (2H, br s), 9.59 (1H, s), 9.34 (2H, brs), 9.04 (2H, br s), 7.89 (2H, d, J = 8.7 Hz), 7.54 (2H, d, J = 8.7 Hz),7.49 (1H, d, J = 3.5 Hz), 6.45 (1H, d, J = 3.5 Hz), 3.70 (4H, s), 2.93(1H, dd, J = 14.6, 7.8 Hz), 2.78-2.70 (2H, m), 1.03 (3H, d, J = 6.6 Hz).MS (ESI) m/z 447 (M + H)+ B-25

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.12 (2H, s), 8.32 (1H, d, J =8.0 Hz), 7.93 (2H, m), 7.74 (2H, m), 7.09 (1H, d, J = 3.6 Hz), 4.50 (1H,m), 3.16 (1H, dd, J = 14.8, 7.6 Hz), 2.90 (1H, dd, J = 14.8, 6.4 Hz),2.75-2.65 (2H, m), 2.55 (1H, dd, J = 8.4, 1.2 Hz), 1.05 (3H, 6.8 Hz). MS(ESl) m/z 466 (M + H)+ B-26

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.15 (2H, s), 8.39 (1H, d, J =8.0 Hz), 7.93 (2H, m), 7.75 (2H, m), 7.10 (1H, d, J = 4.0 Hz), 4.51 (1H,m), 3.07 (1H, dd, J = 14.8, 8.0 Hz), 2.92 (1H, dd, J = 14.8, 6.4 Hz),2.80-2.65 (2H, m), 2.55 (1H, m), 1.50 (2H, m), 1.13 (1H, m), 0.80 (6H,m). MS (ESI) m/z 508 (M + H)+ B-27

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.08 (2H, s), 8.33 (1H, d, J =8.0 Hz), 7.92 (2H, m), 7.73 (2H, m), 7.07 (1H, d, J = 4.4 Hz), 4.53 (1H,m), 3.06 (1H, dd, J = 14.8, 8.4 Hz), 2.93 (1H, dd, J = 14.8, 6.0 Hz),2.80-2.50 (3H, m), 1.55 (2H, m), 1.15 (1H, m), 0.88 (3H, d, J = 6.8 Hz),0.81 (3H, d, J = 6.8 Hz). MS (ESI) m/z 508 (M + H)+ B-28

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.09 (2H, s), 8.33 (1H, m),7.90 (2H, m), 7.74 (2H, m), 7.09 (1H, d, J = 3.6 Hz), 4.48 (1H, m), 3.10(1H, dd, J = 14.8, 8.4 Hz), 2.93 (1H, dd, J = 14.8, 8.0 Hz), 2.75-2.60(2H, m), 2.55 (1H, m), 1.55-1.20 (4H, m), 0.82 (3H, t, J = 6.8 Hz). MS(ESI) m/z 494 (M + H)+ B-29

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.10 (2H, s), 8.29 (1H, m),7.90 (2H, m), 7.74 (2H, m), 7.06 (1H, d, J = 4.0 Hz), 4.53 (1H, m), 3.10(1H, dd, J = 14.8, 6.4 Hz), 2.94 (1H, dd, J = 14.8, 5.6 Hz), 2.75-2.50(3H, m), 1.55- 1.20 (4H, m), 0.85 (3H, t, J = 7.2 Hz). MS (ESI) m/z 494(M + H)+ B-30

1H-NMR (300 MHz, DMSO-d6) δ 9.48 (2H, br s), 9.20 (2H, br s), 8.20 (1H,br s), 7.88 (1H, d, J = 3.8 Hz), 7.79 (1H, dd, J = 8.4, 8.2 Hz), 7.62(1H, d, J = 10.9 Hz), 7.40 (1H, dd, J = 8.4, 2.0 Hz), 7.08 (0.5H, d, J =3.8 Hz), 7.05 (0.5H, d, J = 3.8 Hz), 4.44 (1H, br m), 2.40-3.45 (5H, m),1.07 (1.5H, d, J = 7.1 Hz), 1.05 (1.5H, d, J = 7.9 Hz). MS (ESI) m/z 466(M + H)+ B-31

1H-NMR (300 MHz, DMSO-d6) δ 9.42 (2H, br s), 9.10 (2H, br s), 8.21 (1H,br s), 8.10 (1H, d, J = 2.2 Hz), 7.92 (1H, d, J = 3.8 Hz), 7.86 (1H, dd,J = 8.5, 2.2 Hz), 7.77 (1H, d, J = 8.5 Hz), 7.10 (0.5H, d, J = 3.8 Hz),7.08 (0.5H, d, J = 3.8 Hz), 4.45 (1H, br m), 2.51-3.42 (5H, m), 1.08(1.5H, d, J = 7.0 Hz), 1.06 (1.5H, d, J = 8.2 Hz). MS (ESI) m/z 466 (M +H)+ B-32

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.11 (2H, s), 8.33 (1H, d, J =8.0 Hz), 7.93 (2H, m), 7.73 (2H, m), 7.12 (1H, d, J = 3.6 Hz), 4.55 (1H,m), 3.13 (2H, t, J = 7.2 Hz), 2.68 (1H, dd, J = 12.4, 6.0 Hz), 2.62-2.55(3H, m), MS (ESI) m/z 452 (M + H)+ B-33

1H-NMR (300 MHz, DMSO-d6) δ 9.34 (2H, s), 9.04 (2H, s), 8.35 (0.5H, d, J= 7.8 Hz), 8.29 (0.5H, d, J = 7.8 Hz), 7.91- 7.82 (3H, m), 7.55 (2H, d,J = 7.2 Hz), 7.05 (1H, m), 4.53 (1H, m), 3.15-2.90 (2H, m), 2.75-2.50(3H, m), 1.55-1.18 (4H, m), 0.85 (3H, m). MS (ESI) m/z 476 (M + H) B-34

MS (ESI) m/z 462 (M + H) B-35

1H-NMR (300 MHz, DMSO-d6) δ 9.41 (2H, s), 9.21 (2H, s), 8.15 (1H, m),7.96-7.91 (2H, m), 7.72 (2H, m), 7.10 (1H, m), 4.26 (1H, m), 3.75-3.60(2H, m), 3.22-3.10 (1H, m), 2.96- 2.75 (2H, m), 1.07 (3H, m). MS (ESI)m/z 438 (M + H)+ B-36

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.07 (2H, s), 8.33 (1H, d, J =8.0 Hz), 7.93 (2H, m), 7.73 (2H, m), 7.12 (1H, d, J = 3.6 Hz), 4.55 (1H,m), 3.13 (1H, t, J = 7.6 Hz), 2.68 (1H, dd, J = 12.0, 5.6 Hz), 2.60-2.50(4H, m). MS (ESI) m/z 452 (M + H)+ B-37

1H-NMR (400 MHz, DMSO-d6) δ 9.42 (2H, s), 9.15 (2H, s), 7.93 (2H, m),7.75 (2H, m), 7.16 (0.5H, d, J = 4.0 Hz), 7.13 (0.5H, d, J = 4.0 Hz),4.21 (1H, s), 3.97 (1H, s), 3.60- 3.40 (2H, m), 3.14 (2H, t, J = 6.8Hz), 2.90 (1H, t, J = 6.8 Hz), 2.66 (1H, t, J = 6.8 Hz), 2.54 (1H, t, J= 8.8 Hz), 2.46 (1H, t, J = 6.8 Hz). MS (ESI) m/z 466 (M + H)+ B-38

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.07 (2H, br), 7.96-7.89(2H, m), 7.79-7.70 (2H, m), 7.14 (1H, d, J = 3.6 Hz), 5.92-5.62 (1H, m),5.23-5.06 (2H, m), 4.11- 3.90 (4H, m), 3.21-3.09 (2H, m), 2.84-2.62 (2H,m). MS (ESI) m/z 434 (M + H)+ B-39

1H-NMR (400 MHz, DMSO-d6) δ 9.34 (2H, br), 8.89 (2H, br), 8.22-8.18 (1H,m), 7.90-7.86 (3H, m), 7.60-7.56 (2H, m), 7.12-7.11 (1H, m), 4.39-4.33(1H, m), 3.22-2.60 (5H, m), 1.09-1.06 (3H, m). MS (ESI) m/z 484 (M + H)+B-40

1H-NMR (400 MHz, DMSO-d6) δ 9.45 (2H, br s), 9.20 (2H, br s), 7.98 (1H,br s), 7.85-7.87 (3H, m), 7.50 (1H, br s), 7.08 (1H, d, J = 3.0 Hz),3.17-2.75 (5H, m), 1.05 (3H, d, MS (ESI) m/z 426 (M + H)+ B-41

1H-NMR (400 MHz, DMSO-d6) δ 9.39 (2H, br), 9.09 (2H, br), 8.20 (1H, t, J= 4.7 Hz), 7.94 (1H, d, J = 1.5 Hz), 7.91 (1H, d, J = 3.0 Hz), 7.81-7.72(2H, m), 7.14 (1H, dd, J = 2.9, 1.1 Hz), 4.39-4.33 (1H, m), 3.22-2.63(5H, m), 1.09-1.06 (3H, m). MS (ESI) m/z 502 (M + H)+ B-42

1H-NMR (400 MHz, DMSO-d6) δ 9.43 (2H, br s), 9.34 (2H, br s), 8.09 (1H,br s), 7.93-7.90 (2H, m), 7.75-7.73 (2H, m), 7.10 (1H, d, J = 3.0 Hz),3.26-3.12 (3H, m), 2.88 (1H, dd, J = 11.0, 5.0 Hz), 2.84-2.75 (1H, m),1.05 (3H, d, J = 6.8 Hz), MS (ESI) m/z 444 (M + H)+ B-43

1H-NMR (400 MHz, DMSO-d6) δ 9.42 (2H, s), 9.08 (2H, s), 8.10 (2H, m),7.03 (1H, d, J = 3.6 Hz), 7.86 (1H, dd, J = 8.4, 2.4 Hz), 7.76 (1H, d, J= 8.4 Hz), 7.09 (1H, d, J = 3.6 Hz), 3.20- 3.10 (1H, m), 2.92 (1H, d, J= 14.4 Hz), 2.87 (1H, d, J = 14.4 Hz), 2.79 (2H, m), 1.06 (3H, d, J =6.8). MS (ESI) m/z 460 (M + H)+ B-44

1H-NMR (400 MHz, DMSO-d6) δ 9.03 (2H, s), 8.23 (2H, s), 8.20 (1H, t, J =8.4 Hz), 8.09 (1H, d, J = 1.6 Hz), 7.91 (1H, d, J = 3.8 Hz), 7.92-7.77(2H, m), 7.13 (1H, d, J = 1.6 Hz), 4.37 (1H, m), 3.20-3.10 (1H, m),2.95-2.75 (3H, m), 2.65 (1H, m), 1.08 (3H, m). MS (ESI) m/z 518 (M + H)+B-45

MS (ESI) m/z 502 (M + H)+ B-46

MS (ESI) m/z 444 (M + H)+ B-47

1H-NMR (400 MHz, DMSO-d6) δ 12.04 (1H, br s), 9.35 (2H, br s), 9.02 (2H,br s), 7.92 (1H, d, J = 3.8 Hz), 7.90 (2H, d, J = 8.7 Hz), 7.57 (2H, d,J = 8.7 Hz), 7.08 (1H, d, J = 3.8 Hz), 2.91 (1H, dd, J = 14.6, 6.3 Hz),2.77 (1H, dd, J = 14.6, 7.7 Hz), 2.35-2.19 (2H, m), 1.85-1.76 (1H, m),1.67- 1.58 (1H, m), 1.44-1.35 (1H, m), 0.90 (3H, d, J = 6.6 Hz). MS(ESI) m/z 361 (M + H)+ B-48

1H-NMR (400 MHz, DMSO-d6) δ 12.05 (1H, br s), 9.42 (2H, br s), 9.17 (2H,br s), 7.97 (1H, d, J = 3.8 Hz), 7.93 (1H, dd, J = 10.8, 1.6 Hz),7.79-7.73 (2H, m), 7.11 (1H, d, J = 3.8 Hz), 2.93 (1H, dd, J = 14.6, 6.3Hz), 2.78 (1H, dd, J = 14.6, 7.5 Hz), 2.35-2.20 (2H, m), 1.85-1.77 (1H,m), 1.67- 1.58 (1H, m), 1.44-1.35 (1H, m), 0.90 (3H, d, J = 6.6 Hz). MS(ESI) m/z 379 (M + H)+ B-49

MS (ESI) m/z 494 (M + H)+ B-50

MS (ESI) m/z 476 (M + H)+ B-51

1H-NMR (400 MHz, DMSO-d6) δ 12.37 (1H, br s), 9.41 (2H, br s), 9.18 (2H,br s), 8.53 (1H, d, J = 1.2 Hz), 7.93 (1H, dd, J = 10.6, 1.0 Hz),7.74-7.75 (2H, m), 7.38 (1H, d, J = 1.2 Hz), 3.12 (1H, dd, J = 15.3, 7.8Hz), 2.98 (1H, dd, J = 15.3, 6.0 Hz), 2.71 (1H, m), 1.13 (3H, d, J = 7.2Hz). MS (ESI) m/z 351 (M + H)+ B-52

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.19 (2H, br s), 8.50 (1H,d, J = 1.6 Hz), 8.30 (1H, m), 7.91 (1H, dd, J = 11.6, 1.6 Hz), 7.73 (2H,m), 7.35 (1H, d, J = 3.6 Hz), 4.55- 4.45 (1H, m), 3.10-3.00 (1H, m),2.88-2.50 (4H, m), 1.07 (3H, m). MS (ESI) m/z 466 (M + H)+ B-53

1H-NMR (400 MHz, DMSO-d6) δ 9.33 (2H, s), 9.50 (2H, s), 8.42 (1H, d, J =3.2 Hz), 8.32-8.26 (1H, m), 7.88 (2H, d, J = 6.8 Hz), 7.54 (2H, d, J =6.8 Hz), 7.34 (1H, d, J = 8.4 Hz), 4.50 (1H, m), 3.10-3.00 (1H, m),2.88-2.80 (1H, m), 2.70- 2.55 (3H, m), 1.03 (3H, m). MS (ESI) m/z 448(M + H)+ B-54

1H-NMR (400 MHz, DMSO-d6) δ 9.40 (2H, br s), 9.09 (2H, br s), 8.49 (1H,s), 8.30 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.73 (2H, m),7.38 (1H, s), 4.55 (1H, m), 3.07 (2H, t, J = 7.6 Hz), 2.70-2.55 (4H, m).MS (ESI) m/z 452 (M + H)+ B-55

1H-NMR (300 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.06 (2H, br s), 8.22 (1H,m), 7.90 (3H, m), 7.73 (1H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz),4.55 (1H, m), 2.95-2.80 (1H, m), 2.78-2.55 (4H, m), 1.00 (3H, m). MS(ESI) m/z 448 (M + H)+ B-56

MS (ESI) m/z 482 (M + H)+ B-57

MS (ESI) m/z 500 (M + H)+ B-58

MS (ESI) m/z 482 (M + H)+ B-59

MS (ESI) m/z 488 (M + H)+ B-60

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 8.64 (1H,d, J = 4.0 Hz), 7.98 (2H, m), 7.75 (2H, m), 7.14 (1H, d, J = 3.6 Hz),4.55 (1H, m), 3.90 (2H, s), 3.08- 2.98 (1H, m), 2.70-2.60 (1H, m). MS(ESI) m/z 438 (M + H)+ B-61

1H-NMR (400 MHz, DMSO-d6) δ 9.40 (2H, br s), 9.11 (2H, br s), 8.29 (1H,d, J = 7.2 Hz), 7.92 (1H, d, J = 11.2 Hz), 7.84 (1H, s), 7.77-7.71 (2H,m), 4.57-4.46 (1H, m), 3.03 (2H, t, J = 7.6 Hz), 2.71-2.49 (4H, m), 2.21(3H, s). MS (ESI) m/z 466 (M + H)+ B-62

1H-NMR (400 MHz, DMSO-d6) δ 9.52-9.28 (2H, br s), 9.28-9.03 (2H, br s),8.22 (1H, d, J = 8.0 Hz), 7.96-7.89 (2H, m), 7.78-7.71 (2H, m), 7.12(1H, d, J = 8.0 Hz), 4.22 (1H, td, J = 8.0, 4.2 Hz), 3.15 (2H, t, J =5.4 Hz), 2.63-2.51 (2H, m), 2.29-2.18 (2H, m), 2.01-1.87 (1H, m),1.82-1.69 (1H, m). MS (ESI) m/z 466 (M + H)+ B-63

1H-NMR (400 MHz, DMSO-d6) δ 9.56-9.10 (4H, m), 7.98-7.89 (2H, m),7.79-7.70 (2H, m), 718-7.09 (1H, m), 5.95-5.65 (1H, m), 5.46-4.95 (2H,m), 4.61-4.48 (1H, m), 4.18-3.84 (2H, m), 3.71-2.41 (6H, m). MS (ESI)m/z 492 (M + H)+ B-64

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 7.96-7.89(3H, m), 7.79-7.71 (2H, m), 7.07 (1H, d, J = 4.0 Hz), 4.57 (1H, dt, J =7.2, 6.8 Hz), 3.13 (2H, s), 2.76 (1H, dd, J = 16.4, 6.8 Hz), 2.58 (1H,dd, J = 16.4, 6.8 Hz), 1.14 (3H, s), 1.13 (3H, s). MS (ESI) m/z 480 (M +H)+ B-65

1H-NMR (400 MHz, DMSO-d6) δ 9.42 (2H, br s), 9.24 (1H, br s), 9.16 (2H,br s), 8.24 (1H, d, J = 8.0 Hz), 7.96-7.88 (2H, m), 7.79-7.71 (2H, m),7.00 (1H, d, J = 4.8 Hz), 6.98 (2H, d, J = 8.4 Hz), 6.64 (2H, d, J = 8.4Hz), 4.37 (1H, ddd, J = 9.2, 8.0, 4.8 Hz), 3.07 (2H, t, J = 7.2 Hz),2.93 (1H, dd, J = 14.0, 4.8 Hz), 2.73 (1H, dd, J = 14.0. 9.2 Hz), 2.52(3H, t, J = 12 Hz). MS (ESI) m/z 500 (M + H)+ B-66

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.11 (2H, s), 8.17 (1H, d, J =7.6 Hz), 7.93 (2H, m), 7.75 (2H, m), 7.13 (1H, d, J = 3.6 Hz), 4.31 (1H,m), 3.71-3.66 (1H, m), 3.63-3.58 (1H, m), 3.14 (2H, t, J = 7.2 Hz), 2.62(2H, t, J = 7.2 Hz). MS (ESI) m/z 424 (M + H)+ C-4 

1H-NMR (400 MHz, DMSO-d6) δ 9.42 (2H, s), 9.16 (2H, s), 8.62 (1H, s),8.36 (1H, m), 7.95 (1H, dd, J = 11.0, 2.0 Hz), 7.76 (2H, m), 4.50 (1H,m), 3.30 (1H, m), 3.10-2.85 (1H, m), 2.75-2.55 (3H, m), 1.10 (3H, m). MS(ESI) m/z 467 (M + H)+ C-5 

1H-NMR (400 MHz, DMSO-d6) δ 9.35 (2H, s), 9.02 (2H, s), 8.72 (1H, s),7.91 (2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 4.22 (1H, s), 3.97(1H, s), 3.65-3.30 (4H, m), 2.95 (1H, t, J = 6.8 Hz), 2.75 (1H, t, J =6.8 Hz), 2.55 (1H, t, J = 6.8 Hz), 2.45 (1H, t, J = 6.8 Hz). MS (ESI)m/z 449 (M + H)+

Experimental Example 1 Measurement of Trypsin Inhibitory Activity

Using a 96 well plate (#3915, Costar), a test compound (25 μL) was mixedwith 20 μM fluorescence enzyme substrate (Boc-Phe-Ser-Arg-AMC, 50 μL)mixed with 200 mM Tris-HCl buffer (pH 8.0), and human trypsin (Sigma, 25μL) was added. Using a fluorescence plate reader fmax (MolecularDevices, Inc.), the reaction rate was measured from the time-coursechanges at excitation wavelength 355 nm and fluorescence wavelength 460nm. The Ki value was calculated from the concentration of the testcompound, reciprocal of reaction rate, and Km value of the enzymesubstrate, and by using Dixon plot. The results are shown in Table 3.

Experimental Example 2 Measurement of Enteropeptidase InhibitoryActivity

Using a 96 well plate (#3915, Costar), a test compound (25 μL), 400 mMTris-HCl buffer (pH 8.0, 25 μL) and 0.5 mg/mL fluorescence enzymesubstrate (Gly-Asp-Asp-Asp-Asp-Lys-β-Naphtylamide, 25 μL) were mixed,and recombinant human enteropeptidase (R&D Systems, Inc., 25 μL) wasadded. Using a fluorescence plate reader fmax (Molecular Devices, Inc.),the reaction rate was measured from the time-course changes atexcitation wavelength 320 nm and fluorescence wavelength 405 nm. The Kivalue was calculated from the concentration of the test compound,reciprocal of reaction rate, and Km value of the enzyme substrate, andby using Dixon plot. The results are shown in Table 3.

TABLE 3 Enteropeptidase Trypsin inhibitory Compound inhibitory activityactivity No. Ki (nM) Ki (nM) A-1 2.27 0.52 A-2 1.97 0.44 A-3 1.15 0.69A-4 2.68 1.26 A-5 1.37 1.13 A-6 0.62 1.53 A-7 1.49 1.01 A-9 3.17 7.32A-10 6.73 9.15 A-12 3.31 1.13 A-14 3.52 0.48 A-15 1.63 1.16 A-16 1.881.84 A-17 2.43 1.76 A-18 0.61 1.07 A-19 1.91 2.92 A-20 2.54 1.88 A-214.81 3.25 A-22 0.95 2.0 A-23 2.0 1.3 A-24 1.9 2.4 A-25 2.1 2.0 A-26 0.682.29 A-27 0.57 0.95 A-28 0.42 0.75 A-29 0.82 1.67 A-30 1.03 1.28 A-310.50 0.62 A-32 0.62 2.89 A-33 0.65 0.79 A-34 0.98 1.65 A-35 0.25 0.38A-36 0.58 1.33 A-37 0.64 1.46 A-38 0.57 0.86 A-39 0.67 1.60 A-41 0.500.89 A-42 0.71 3.8 A-43 0.40 0.52 A-44 0.33 0.62 A-45 0.46 0.97 A-460.35 0.47 A-47 1.9 5.7 A-48 1.3 4.5 A-49 7.6 3.4 A-50 4.4 2.3 A-51 4.93.6 A-52 2.5 1.2 A-54 0.60 1.3 A-55 1.3 1.4 A-56 1.1 1.7 A-57 0.39 2.0A-58 0.70 0.72 A-59 0.35 0.12 A-60 0.31 6.7 A-61 0.42 3.7 A-62 2.1 4.2A-63 0.53 0.92 A-64 2.5 3.1 A-65 1.0 4.5 A-66 0.32 0.44 A-67 0.52 0.20A-68 2.2 0.23 A-69 4.7 0.62 A-70 2.7 0.30 A-71 1.6 0.054 A-72 0.68 2.3A-73 0.88 0.53 A-74 2.6 3.8 B-2 9.29 6.34 B-3 5.72 4.76 B-6 1.44 7.19B-7 2.15 7.36 B-8 0.84 0.22 B-11 1.41 2.39 B-12 2.21 5.75 B-16 0.29 1.51B-17 0.42 1.76 B-18 1.36 1.76 B-19 0.42 0.91 B-20 0.28 0.18 B-21 0.560.15 B-22 0.50 0.39 B-23 1.47 1.54 B-24 0.49 0.83 B-25 0.79 0.19 B-262.2 1.0 B-27 0.95 1.3 B-28 1.1 0.43 B-29 0.58 1.3 B-30 0.52 0.33 B-310.33 0.66 B-32 0.31 0.48 B-33 2.8 3.6 B-34 2.2 2.7 B-35 0.40 0.97 B-360.51 0.84 B-37 0.50 4.5 B-38 0.75 1.4 B-39 0.95 2.2 B-40 2.0 1.8 B-410.27 0.21 B-42 0.37 0.22 B-43 0.42 0.49 B-44 0.21 0.57 B-45 0.48 1.1B-46 0.38 0.44 B-47 2.5 1.8 B-48 0.88 0.37 B-49 0.41 0.18 B-50 0.89 0.47B-51 0.72 1.6 B-52 0.39 0.51 B-53 4.8 8.5 B-54 0.58 0.79 B-55 0.98 5.0B-56 9.5 0.70 B-57 3.0 0.27 B-58 9.8 3.5 B-59 8.2 4.4 B-60 0.64 3.2 B-610.13 0.5 B-62 0.57 0.4 B-63 0.55 0.9 B-64 0.14 0.6 B-65 3.20 3.7 B-660.73 1.2 C-2 5.67 0.39 C-4 3.7 0.2

Thus, the compound of the present invention was confirmed to showsuperior enteropeptidase inhibitory activity and superior trypsininhibitory activity. Therefore, it has been shown that the compound ofthe present invention having an inhibitory activity on enteropeptidaseand trypsin decreases digestive capacity for protein, lipid, andcarbohydrates, and is effective as a therapeutic and prophylactic drugfor obesity and hyperlipidemia.

Experimental Example 3 Evaluation of Antidiabetic Action

KK-A^(y)/JCL mice (male, 5- to 7-week-old, CLEA Japan, Inc.) known tospontaneously develop obese type 2 diabetes were purchased and, afterone week of preliminary rearing period, grouped (6 per group) with thebody weight and non-fasting blood glucose levels as indices. The animalswere individually housed in a polycarbonate cage and allowed to drinkwater freely from a watering bottle. During the test period, they wereallowed to freely ingest a mixture of a test compound (B-18hydrochloride, B-20 hydrochloride, A-28 hydrochloride, B-23hydrochloride, or B-32 hydrochloride) (5.6 mg/100 g or 16.8 mg/100 g)and powder feed CRF-1 (Oriental Yeast Co., Ltd.). CRF-1 alone was givento the control group. After one week of dosing period, the blood (6 μL)was drawn from the tail vein of the animals, and the blood glucose levelwas measured by ACCU-CHEK Aviva (Roche Diagnostics K.K.). The resultsare shown in Table 4. A significant difference from the control groupwas detected by Dunnett's multiple comparison test or Student's t-test(significance level less than 5%). Thus, the test compound showed asignificant hypoglycemic action. The compound of the present inventionhaving an enteropeptidase inhibitory activity and a trypsin inhibitoryactivity was shown to have a blood glucose elevation suppressing orhypoglycemic action. In addition, it has also been shown that thecompound of the present invention shows an insulin sensitizing activityand is also useful as a prophylactic or therapeutic agent for obesity,diabetic complications, or metabolic syndrome, since it shows a bloodglucose elevation suppressing or hypoglycemic action.

TABLE 4 Mean blood Dose glucose level Standard (mg/100 g) (mg/dL) errorp value Control group 447 22 B-18 5.6 217 40 <0.001 hydrochloride B-1816.8 138 7 <0.001 hydrochloride Control group 415 27 B-20 5.6 197 27<0.001 hydrochloride A-28 5.6 219 46 <0.001 hydrochloride B-23 5.6 19823 <0.001 hydrochloride Control group 478 28 B-32 5.6 249 39 <0.001hydrochloride

INDUSTRIAL APPLICABILITY

The trypsin and enteropeptidase inhibitory compound relating to thepresent invention can be used as an active ingredient of a therapeuticor prophylactic drug of diabetes or diabetic complications.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. (canceled)
 2. A method for inhibiting serine protease, comprising:administering an effective amount of a compound represented by formula(I):

or a pharmaceutically acceptable salt thereof to a subject in needthereof, wherein R1, R2, R3, and R4 may be the same or different and areeach independently a hydrogen atom, a nitro group, a halogeno group, acyano group, a hydroxyl group, a thiol group, an amino group, aguanidino group, a formyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a lower acyl group, a carboxyl group, asulfo group, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower acyloxy group, a loweracylamino group, a lower alkoxycarbonyl group, a carbamoyl group, alower alkylcarbamoyl group, a lower alkylsulfonylamino group, or asulfamoyl group, HetAr is a furan ring optionally having substituent(s),X is a lower alkylene group optionally having substituent(s), a loweralkenylene group optionally having substituent(s), a lower alkynylenegroup optionally having substituent(s), or a thiophenylene group, Y is acarbonyl group, a thiocarbonyl group, or a sulfonyl group, and A is agroup of formula (II):

 where R6 and R7 may be the same or different and are each independentlya hydrogen atom, a hydroxyl group, a lower alkyl group optionally havingsubstituent(s), a lower alkenyl group optionally having substituent(s),a lower alkynyl group optionally having substituent(s), or a loweralkoxyl group optionally having substituent(s), or R6 and R7 may bebonded to form a cyclic amino group optionally having substituent(s). 3.A method according to claim 2, wherein X is a lower alkylene groupoptionally having substituent(s), a lower alkenylene group optionallyhaving substituent(s), or a lower alkynylene group optionally havingsubstituent(s).
 4. A method according to claim 2, wherein R1, R2, R3,and R4 are each independently a hydrogen atom, a nitro group, or ahalogeno group.
 5. A method according to claim 2, wherein -HetAr- is aheteroaromatic ring group represented by formula (III-1) or (III-2):

where Z1 and Z2 are each independently CRa, and Z3 is an oxygen atom,and each Ra may be the same or different and is independently a hydrogenatom, a nitro group, a halogeno group, a cyano group, a hydroxyl group,a thiol group, an amino group, a guanidino group, a formyl group, alower alkyl group, a lower alkenyl group, a lower alkynyl group, a loweracyl group, a carboxyl group, a sulfo group, a phosphono group, a loweralkoxyl group, a lower alkylthio group, a lower alkylamino group, alower acyloxy group, a lower acylamino group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, or a sulfamoyl group.
 6. A method according toclaim 2, wherein X is a lower alkylene group optionally havingsubstituent(s) or a lower alkenylene group optionally havingsubstituent(s), wherein said substituent(s) is selected from the groupconsisting of a halogeno group, a hydroxyl group, an amino group, alower alkyl group, a lower alkoxyl group, and a lower acyl group.
 7. Amethod according to claim 2, wherein Y is a carbonyl group or a sulfonylgroup.
 8. A method according to claim 2, wherein A is a group of formula(IV):

where R60 is a carboxyl group, a sulfo group, a phosphono group, a loweralkoxycarbonyl group, or a hydroxyl group, D is a lower alkylene groupoptionally having substituent(s), a lower alkenylene group optionallyhaving substituent(s), or a lower alkynylene group optionally havingsubstituent(s), wherein said substituent(s) is selected from the groupconsisting of a nitro group, a halogeno group, a cyano group, a hydroxylgroup, a thiol group, an amino group, a guanidino group, a formyl group,a lower acyl group, a carboxyl group, a sulfo group, a phosphono group,a lower alkoxyl group, a lower alkylthio group, a lower alkylaminogroup, a lower acyloxy group, a lower acylamino group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, alower alkylsulfonylamino group, an arylsulfonylamino group optionallyhaving substituent(s), a cycloalkyl group optionally havingsubstituent(s), an aryl group optionally having substituent(s), anaryloxy group optionally having substituent(s), an arylthio groupoptionally having substituent(s), an aralkyl group optionally havingsubstituent(s), an aralkyloxy group optionally having substituent(s), anaralkylthio group optionally having substituent(s), a heterocyclic groupoptionally having substituent(s), a heterocyclic oxy group optionallyhaving substituent(s), a heterocyclic thio group optionally havingsubstituent(s), and an oxo group, and R70 is a hydrogen atom, a hydroxylgroup, a lower alkyl group optionally having substituent(s), or a loweralkoxyl group optionally having substituent(s), or R70 and D may bebonded to form a cyclic amino group optionally having substituent(s). 9.A method according to claim 2, wherein R60 is a carboxyl group, a sulfogroup, a lower alkoxycarbonyl group, or a hydroxyl group, D is a loweralkylene group optionally having substituent(s), wherein saidsubstituent(s) is selected from the group consisting of a halogenogroup, a hydroxyl group, a thiol group, an amino group, a guanidinogroup, a carboxyl group, a sulfo group, a lower alkoxyl group, a loweralkylthio group, a lower alkylamino group, a lower acylamino group, alower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoylgroup, a lower alkylsulfonylamino group, an arylsulfonylamino groupoptionally having substituent(s), an aryl group optionally havingsubstituent(s), a heterocyclic group optionally having substituent(s),and an oxo group, and R70 is a hydrogen atom, a hydroxyl group, a loweralkyl group optionally having substituent(s), or a lower alkoxyl groupoptionally having substituent(s), or R70 and D may be bonded to form acyclic amino group optionally having substituent(s).
 10. A methodaccording to claim 2, wherein R1, R2, R3, and R4 are each independentlya hydrogen atom, a nitro group, or a fluorine atom, and HetAr is furanoptionally having substituent(s).
 11. A method for inhibiting intestinalserine protease, comprising: administering an effective amount of acompound represented by formula (I):

or a pharmaceutically acceptable salt thereof to a subject in needthereof, wherein R1, R2, R3, and R4 may be the same or different and areeach independently a hydrogen atom, a nitro group, a halogeno group, acyano group, a hydroxyl group, a thiol group, an amino group, aguanidino group, a formyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a lower acyl group, a carboxyl group, asulfo group, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower acyloxy group, a loweracylamino group, a lower alkoxycarbonyl group, a carbamoyl group, alower alkylcarbamoyl group, a lower alkylsulfonylamino group, or asulfamoyl group, HetAr is a furan ring optionally having substituent(s),X is a lower alkylene group optionally having substituent(s), a loweralkenylene group optionally having substituent(s), a lower alkynylenegroup optionally having substituent(s), or a thiophenylene group, Y is acarbonyl group, a thiocarbonyl group, or a sulfonyl group, and A is agroup of formula (II):

where R6 and R7 may be the same or different and are each independentlya hydrogen atom, a hydroxyl group, a lower alkyl group optionally havingsubstituent(s), a lower alkenyl group optionally having substituent(s),a lower alkynyl group optionally having substituent(s), or a loweralkoxyl group optionally having substituent(s), or R6 and R7 may bebonded to form a cyclic amino group optionally having substituent(s).12. A method according to claim 11, wherein X is a lower alkylene groupoptionally having substituent(s), a lower alkenylene group optionallyhaving substituent(s), or a lower alkynylene group optionally havingsubstituent(s).
 13. A method according to claim 11, wherein R1, R2, R3,and R4 are each independently a hydrogen atom, a nitro group, or ahalogeno group.
 14. A method according to claim 11, wherein -HetAr- is aheteroaromatic ring group represented by formula (III-1) or (III-2):

where Z1 and Z2 are each independently CRa, and Z3 is an oxygen atom,and each Ra may be the same or different and is independently a hydrogenatom, a nitro group, a halogeno group, a cyano group, a hydroxyl group,a thiol group, an amino group, a guanidino group, a formyl group, alower alkyl group, a lower alkenyl group, a lower alkynyl group, a loweracyl group, a carboxyl group, a sulfo group, a phosphono group, a loweralkoxyl group, a lower alkylthio group, a lower alkylamino group, alower acyloxy group, a lower acylamino group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, or a sulfamoyl group.
 15. A method accordingto claim 11, wherein X is a lower alkylene group optionally havingsubstituent(s) or a lower alkenylene group optionally havingsubstituent(s), wherein said substituent(s) is selected from the groupconsisting of a halogeno group, a hydroxyl group, an amino group, alower alkyl group, a lower alkoxyl group, and a lower acyl group.
 16. Amethod according to claim 11, wherein Y is a carbonyl group or asulfonyl group.
 17. A method according to claim 11, wherein A is a groupof formula (IV):

where R60 is a carboxyl group, a sulfo group, a phosphono group, a loweralkoxycarbonyl group, or a hydroxyl group, D is a lower alkylene groupoptionally having substituent(s), a lower alkenylene group optionallyhaving substituent(s), or a lower alkynylene group optionally havingsubstituent(s), wherein said substituent(s) is selected from the groupconsisting of a nitro group, a halogeno group, a cyano group, a hydroxylgroup, a thiol group, an amino group, a guanidino group, a formyl group,a lower acyl group, a carboxyl group, a sulfo group, a phosphono group,a lower alkoxyl group, a lower alkylthio group, a lower alkylaminogroup, a lower acyloxy group, a lower acylamino group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, alower alkylsulfonylamino group, an arylsulfonylamino group optionallyhaving substituent(s), a cycloalkyl group optionally havingsubstituent(s), an aryl group optionally having substituent(s), anaryloxy group optionally having substituent(s), an arylthio groupoptionally having substituent(s), an aralkyl group optionally havingsubstituent(s), an aralkyloxy group optionally having substituent(s), anaralkylthio group optionally having substituent(s), a heterocyclic groupoptionally having substituent(s), a heterocyclic oxy group optionallyhaving substituent(s), a heterocyclic thio group optionally havingsubstituent(s), and an oxo group, and R70 is a hydrogen atom, a hydroxylgroup, a lower alkyl group optionally having substituent(s), or a loweralkoxyl group optionally having substituent(s), or R70 and D may bebonded to form a cyclic amino group optionally having substituent(s).18. A method according to claim 11, wherein R60 is a carboxyl group, asulfo group, a lower alkoxycarbonyl group, or a hydroxyl group, D is alower alkylene group optionally having substituent(s), wherein saidsubstituent(s) is selected from the group consisting of a halogenogroup, a hydroxyl group, a thiol group, an amino group, a guanidinogroup, a carboxyl group, a sulfo group, a lower alkoxyl group, a loweralkylthio group, a lower alkylamino group, a lower acylamino group, alower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoylgroup, a lower alkylsulfonylamino group, an arylsulfonylamino groupoptionally having substituent(s), an aryl group optionally havingsubstituent(s), a heterocyclic group optionally having substituent(s),and an oxo group, and R70 is a hydrogen atom, a hydroxyl group, a loweralkyl group optionally having substituent(s), or a lower alkoxyl groupoptionally having substituent(s), or R70 and D may be bonded to form acyclic amino group optionally having substituent(s).
 19. A methodaccording to claim 11, wherein R1, R2, R3, and R4 are each independentlya hydrogen atom, a nitro group, or a fluorine atom, and HetAr is furanoptionally having substituent(s).
 20. A method for inhibiting trypsinand enteropeptidase, comprising: administering an effective amount of acompound represented by formula (I):

or a pharmaceutically acceptable salt thereof to a subject in needthereof, wherein R1, R2, R3, and R4 may be the same or different and areeach independently a hydrogen atom, a nitro group, a halogeno group, acyano group, a hydroxyl group, a thiol group, an amino group, aguanidino group, a formyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a lower acyl group, a carboxyl group, asulfo group, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower acyloxy group, a loweracylamino group, a lower alkoxycarbonyl group, a carbamoyl group, alower alkylcarbamoyl group, a lower alkylsulfonylamino group, or asulfamoyl group, HetAr is a furan ring optionally having substituent(s),X is a lower alkylene group optionally having substituent(s), a loweralkenylene group optionally having substituent(s), a lower alkynylenegroup optionally having substituent(s), or a thiophenylene group, Y is acarbonyl group, a thiocarbonyl group, or a sulfonyl group, and A is agroup of formula (II):

where R6 and R7 may be the same or different and are each independentlya hydrogen atom, a hydroxyl group, a lower alkyl group optionally havingsubstituent(s), a lower alkenyl group optionally having substituent(s),a lower alkynyl group optionally having substituent(s), or a loweralkoxyl group optionally having substituent(s), or R6 and R7 may bebonded to form a cyclic amino group optionally having substituent(s).21. A method according to claim 20, wherein X is a lower alkylene groupoptionally having substituent(s), a lower alkenylene group optionallyhaving substituent(s), or a lower alkynylene group optionally havingsubstituent(s).
 22. A method according to claim 20, wherein R1, R2, R3,and R4 are each independently a hydrogen atom, a nitro group, or ahalogeno group.
 23. A method according to claim 20, wherein -HetAr- is aheteroaromatic ring group represented by formula (III-1) or (III-2):

where Z1 and Z2 are each independently CRa, and Z3 is an oxygen atom,and each Ra may be the same or different and is independently a hydrogenatom, a nitro group, a halogeno group, a cyano group, a hydroxyl group,a thiol group, an amino group, a guanidino group, a formyl group, alower alkyl group, a lower alkenyl group, a lower alkynyl group, a loweracyl group, a carboxyl group, a sulfo group, a phosphono group, a loweralkoxyl group, a lower alkylthio group, a lower alkylamino group, alower acyloxy group, a lower acylamino group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, or a sulfamoyl group.
 24. A method accordingto claim 20, wherein X is a lower alkylene group optionally havingsubstituent(s) or a lower alkenylene group optionally havingsubstituent(s), wherein said substituent(s) is selected from the groupconsisting of a halogeno group, a hydroxyl group, an amino group, alower alkyl group, a lower alkoxyl group, and a lower acyl group.
 25. Amethod according to claim 20, wherein Y is a carbonyl group or asulfonyl group.
 26. A method according to claim 20, wherein A is a groupof formula (IV):

where R60 is a carboxyl group, a sulfo group, a phosphono group, a loweralkoxycarbonyl group, or a hydroxyl group, D is a lower alkylene groupoptionally having substituent(s), a lower alkenylene group optionallyhaving substituent(s), or a lower alkynylene group optionally havingsubstituent(s), wherein said substituent(s) is selected from the groupconsisting of a nitro group, a halogeno group, a cyano group, a hydroxylgroup, a thiol group, an amino group, a guanidino group, a formyl group,a lower acyl group, a carboxyl group, a sulfo group, a phosphono group,a lower alkoxyl group, a lower alkylthio group, a lower alkylaminogroup, a lower acyloxy group, a lower acylamino group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, alower alkylsulfonylamino group, an arylsulfonylamino group optionallyhaving substituent(s), a cycloalkyl group optionally havingsubstituent(s), an aryl group optionally having substituent(s), anaryloxy group optionally having substituent(s), an arylthio groupoptionally having substituent(s), an aralkyl group optionally havingsubstituent(s), an aralkyloxy group optionally having substituent(s), anaralkylthio group optionally having substituent(s), a heterocyclic groupoptionally having substituent(s), a heterocyclic oxy group optionallyhaving substituent(s), a heterocyclic thio group optionally havingsubstituent(s), and an oxo group, and R70 is a hydrogen atom, a hydroxylgroup, a lower alkyl group optionally having substituent(s), or a loweralkoxyl group optionally having substituent(s), or R70 and D may bebonded to form a cyclic amino group optionally having substituent(s).27. A method according to claim 20, wherein R60 is a carboxyl group, asulfo group, a lower alkoxycarbonyl group, or a hydroxyl group, D is alower alkylene group optionally having substituent(s), wherein saidsubstituent(s) is selected from the group consisting of a halogenogroup, a hydroxyl group, a thiol group, an amino group, a guanidinogroup, a carboxyl group, a sulfo group, a lower alkoxyl group, a loweralkylthio group, a lower alkylamino group, a lower acylamino group, alower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoylgroup, a lower alkylsulfonylamino group, an arylsulfonylamino groupoptionally having substituent(s), an aryl group optionally havingsubstituent(s), a heterocyclic group optionally having substituent(s),and an oxo group, and R70 is a hydrogen atom, a hydroxyl group, a loweralkyl group optionally having substituent(s), or a lower alkoxyl groupoptionally having substituent(s), or R70 and D may be bonded to form acyclic amino group optionally having substituent(s).
 28. A methodaccording to claim 20, wherein R1, R2, R3, and R4 are each independentlya hydrogen atom, a nitro group, or a fluorine atom, and HetAr is furanoptionally having substituent(s).